WO2004016608A1 - Novel quinuclidine derivatives and their use - Google Patents

Novel quinuclidine derivatives and their use Download PDF

Info

Publication number
WO2004016608A1
WO2004016608A1 PCT/DK2003/000538 DK0300538W WO2004016608A1 WO 2004016608 A1 WO2004016608 A1 WO 2004016608A1 DK 0300538 W DK0300538 W DK 0300538W WO 2004016608 A1 WO2004016608 A1 WO 2004016608A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkoxy
alkyl
aza
octane
bicyclo
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/DK2003/000538
Other languages
English (en)
French (fr)
Inventor
Dan Peters
Gunnar M. Olsen
Elsebet Østergaard NIELSEN
Philip K. Ahring
Tino Dyhring Jørgensen
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
NTG Nordic Transport Group AS
Original Assignee
Neurosearch AS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to BR0313153-0A priority Critical patent/BR0313153A/pt
Priority to UAA200500621A priority patent/UA78812C2/uk
Priority to NZ538058A priority patent/NZ538058A/en
Priority to CA002493245A priority patent/CA2493245A1/en
Priority to EP03787742A priority patent/EP1532144B1/en
Priority to HK06100949.6A priority patent/HK1080860B/xx
Priority to AU2003250322A priority patent/AU2003250322B2/en
Priority to DE60318860T priority patent/DE60318860T2/de
Priority to JP2005502013A priority patent/JP2005538187A/ja
Priority to US10/522,150 priority patent/US20050245567A1/en
Priority to MXPA05001702A priority patent/MXPA05001702A/es
Application filed by Neurosearch AS filed Critical Neurosearch AS
Publication of WO2004016608A1 publication Critical patent/WO2004016608A1/en
Priority to AT04741916T priority patent/ATE496050T1/de
Priority to PCT/EP2004/051283 priority patent/WO2005016923A1/en
Priority to US10/568,148 priority patent/US7750022B2/en
Priority to EP04741916A priority patent/EP1656375B1/en
Priority to DE602004031124T priority patent/DE602004031124D1/de
Priority to IL16625405A priority patent/IL166254A0/xx
Anticipated expiration legal-status Critical
Priority to NO20051264A priority patent/NO20051264L/no
Priority to IS7742A priority patent/IS7742A/is
Priority to US12/206,302 priority patent/US20090005390A1/en
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/06—Antiabortive agents; Labour repressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • This invention relates to novel quinuclidine derivatives and their use as pharmaceuticals. Due to their pharmacological profile the compounds of the invention may be useful for the treatment of diseases or disorders as diverse as those related to the cholinergic system of the central nervous system (CNS), the peripheral nervous system (PNS), diseases or disorders related to smooth muscle contraction, endocrine diseases or disorders, diseases or disorders related to neuro-degeneration, diseases or disorders related to inflammation, pain, and withdrawal symptoms caused by the termination of abuse of chemical substances.
  • CNS central nervous system
  • PNS peripheral nervous system
  • acetylcholine exerts its biological effect via two types of cholinergic receptors, the muscarinic Acetyl Choline Receptors (mAChR) and the nicotinic Acetyl Choline Receptors (nAChR).
  • mAChR muscarinic Acetyl Choline Receptors
  • nAChR nicotinic Acetyl Choline Receptors
  • muscarinic acetylcholine receptors are of importance in relation to memory and cognition, and much research aimed at the development of agents for the treatment of memory related disorders have focused on the synthesis of muscarinic acetylcholine receptor modulators.
  • Cyclase-Lanosterol Synthase Optimization from Lipid Profiles; J. Med. Chem. 1999 42 1306-1311] describe the synthesis of 3-substituted quinuclidine derivatives useful as inhibitors of the cholesterol biosynthesis. An effect on the nicotinic and/or the monoamine receptors is not reported.
  • the present invention is devoted to the provision of new quinuclidine derivatives that are modulators of the nicotinic and/or of the monoamine receptors, and which modulators are useful for the treatment of diseases or disorders related to the cholinergic receptors, and in particular the nicotinic acetylcholine receptor, the monoamine receptors, in particular the serotonin receptor (5-HTR), the dopamine receptor (DAR) and the norepinephrine receptor (NER), and of the biogenic amine transporters for serotonin (5-HT), dopamine (DA) and norepinephrine (NE).
  • 5-HTR serotonin receptor
  • DAR dopamine receptor
  • NER norepinephrine receptor
  • the compounds of the invention may be useful for the treatment of diseases or disorders as diverse as those related to the cholinergic system of the central nervous system (CNS), the peripheral nervous system (PNS), diseases or disorders related to smooth muscle contraction, endocrine diseases or disorders, diseases or disorders related to neuro-degeneration, diseases or disorders related to inflammation, pain, and withdrawal symptoms caused by the termination of abuse of chemical substances.
  • CNS central nervous system
  • PNS peripheral nervous system
  • the compounds of the invention may also be useful as diagnostic tools or monitoring agents in various diagnostic methods, and in particular for in vivo receptor imaging (neuroimaging), and they may be used in labelled or unlabelled form.
  • n 1 , 2 or 3;
  • A represents a monocyclic or polycyclic, carbocyclic or heterocyclic group, optionally substituted one or more times with substituents selected from the group consisting of alkyl, cycloalkyl, cycloalkyl-alkyl, alkoxy, hydroxyalkoxy, alkoxy-alkyl, alkoxy-alkoxy, cycloalkoxy, cycloalkoxy-alkyl, cycloalkoxy-alkoxy, halo, CF 3 , CN, NO 2> NH 2 , carboxy, carbamoyl, amido, sulfamoyl, and phenyl, or with another monocyclic or polycyclic, carbocyclic or heterocyclic group, which additional monocyclic or polycyclic, carbocyclic or heterocyclic group may optionally be substituted one or more times with substituents selected from the group consisting of alkyl, cycloalkyl, cycloalkyl-alkyl, alkoxy, hydroxy
  • the invention provides pharmaceutical compositions comprising a therapeutically effective amount of the quinuclidine derivative of the invention.
  • the invention relates to the use of the quinuclidine derivative of the invention, or a pharmaceutically-acceptable addition salt thereof, for the manufacture of a pharmaceutical composition/medicament for the treatment, prevention or alleviation of a disease or a disorder or a condition of a mammal, includ- ing a human, which disease, disorder or condition is responsive to the action of a nicotinic acetylcholine receptor modulator.
  • the invention provides a method of the treatment or alleviation of a disease or disorder of a living animal body, including a human, which disease or disorder is responsive to the action of a nicotinic acetylcholine receptor modulator, which method comprises the step of administering to such a living animal body, including a human, in need thereof a therapeutically effective amount of the quinuclidine derivative of the invention.
  • the present invention provides novel quinuclidine derivatives represented by Formula I
  • n 1, 2 or 3;
  • A represents a monocyclic or polycyclic, carbocyclic or heterocyclic group, optionally substituted one or more times with substituents selected from the group consisting of alkyl, cycloalkyl, cycloalkyl-alkyl, alkoxy, hydroxyalkoxy, alkoxy-alkyl, alkoxy-alkoxy, cycloalkoxy, cycloalkoxy-alkyl, cycloalkoxy-alkoxy, halo, CF 3 , CN, NO 2 , NH 2 , carboxy, carbamoyl, amido, sulfamoyl, and phenyl, or with another monocyclic or polycyclic, carbocyclic or heterocyclic group, which additional monocyclic or polycyclic, carbocyclic or heterocyclic group may optionally be substituted one or more times with substituents selected from the group consisting of alkyl, cycloalkyl, cycloalkyl-alkyl, alkoxy,
  • the quinuclidine derivative of the invention is a compound of Formula I, wherein represents a single (covalent) bond.
  • the quinuclidine derivative of the invention is a compound of Formula I, wherein n is 1, 2 or 3.
  • the quinuclidine derivative of the invention is a compound of Formula I, wherein X represents a linker selected from -O-, -O-CH 2 -, -O-CH2-CH2-- -S-, and -CH 2 -. In a more preferred embodiment X represents a linker selected from -O-, -O-CH 2 -. and -O-CH 2 -CH 2 -.
  • the quinuclidine derivative of the invention is a compound of Formula I, wherein A represents a monocyclic or polycyclic carbocyclic group selected from phenyl; indanyl, in particular 4-indanyl and 5-indanyl; indenyl, in particular 1-indenyl, 2-indenyl and 3-indenyl; naphthyl, in particular 1- naphthyl and 2-naphthyl; 5,6,7,8-tetrahydro-naphthyl, in particular 5,6,7, 8-tetrahydro-1- naphthyl and 5,6,7,8-tetrahydro-2-naphthyl; , azulenyl, in particular 1-azulenyl, 2- azulenyl and 3-azulenyl; and fluorenyl, in particular 1-fluorenyl, 2-fluorenyl, 3-fluorenyl and 4-fluorenyl; and
  • the quinuclidine derivative of the invention is a compound of Formula I, wherein A represents an aromatic monocyclic or polycyclic carbocyclic group selected from phenyl; indenyl, in particular 1-indenyl, 2-indenyl and 3-indenyl; naphthyl, in particular 1 -naphthyl and 2-naphthyl; azulenyl, in particular 1- azulenyl, 2-azulenyl and 3-azulenyl; and anthracenyl, in particular 1 -anthracenyl and 2- anthracenyl; which aromatic carbocyclic group is optionally substituted one Or two times with substituents selected from the group consisting of alkyl, cycloalkyl, cycloalkyl-alkyl, alkoxy, hydroxyalkoxy, alkoxy-alkyl, alkoxy-alkoxy, cycloalkoxy, cycloalkoxy-
  • the quinuclidine derivative of the invention of Formula I is (+)-3-(2-Phenylphenyloxy)-1-aza-bicyclo[2.2.2]octane;
  • the quinuclidine derivative of the invention is a compound of Formula I, wherein A represents a monocyclic or polycyclic heterocyclic group selected from pyridyl, in particular pyrid-2-yl, pyrid-3-yl and pyrid-4- yl; thienyl, in particular thien-2-yl and thien-3-yl; furanyl, in particular furan-2-yl and furan-3-yl; pyridazinyl, in particular pyridazin-3-yl and pyridazin-4-yl; thiazolyl, in particular thiazol-2-yl, thiazol-4-yl and thiazol-5-yl; thiadiazolyl, in particular 1 ,3,4- thiadiazol-2-yl, 1 ,3,4-thiadiazol-5-yl, 1 ,2,4-thiadiazol-3-yl and 1 ,2,4-thiadiazol-5
  • the quinuclidine derivative of the invention is a compound of Formula I, wherein A represents a monocyclic heterocyclic group selected from pyridyl, in particular pyrid-2-yl, pyrid-3-yl and pyrid-4-yl; thienyl, in particular thien-2-yl and thien-3-yl; furanyl, in particular furan-2-yl and furan-3-yl; pyridazinyl, in particular pyridazin-3-yl and pyridazin-4-yl; thiazolyl, in particular thiazol- 2-yl, thiazol-4-yl and thiazol-5-yl; thiadiazolyl, in particular 1 ,3,4-thiadiazol-2-yl, 1 ,3,4- thiadiazol-5-yl, 1,2,4-thiadiazol-3-yl and 1 ,2,4-thiadiazol-5-yl; which monocycl
  • the quinuclidine derivative of the invention is a compound of Formula I, wherein A represents a polycyclic heterocyclic group selected from indolyl, in particular indol-2-yl and indol-3-yl; isoindolyl, in particular isoindol-2-yl; quinolinyl, in particular quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin- 5-yl and quinolin-6-yl; quinoxalinyl, in particular quinoxalin-2-yl and quinoxalin-3-yl; benzimidazolyl, in particular benzimidazol-2-yl; benzoxazolyl, in particular benzoxazol- 2-yl; benzthiazolyl, in particular benzthiazol-2-yl; benzisothiazolyl, in particular benzisothiazol-3-yl; benztriazolyl, in particular 1 ,
  • the quinuclidine derivative of the invention of Formula I is ( ⁇ )-3-[(1 ,3-Dione)-2- ⁇ soindolyl-methoxy]-1-azabicyclo[2.2.2]octane;
  • the quinuclidine derivative of the invention is a compound of Formula II wherein represents an optional double bond; n is 1 , 2 or 3; X represents a linker selected from -O-, -O-CH2-, -O-CH2-CH2-, -S-, -SO-,
  • Y represents O, S, SO 2 , or NR', wherein R' represents hydrogen or alkyl.
  • the quinuclidine derivative of the invention is a compound of Formula II, wherein represents a single (covalent) bond.
  • the quinuclidine derivative of the invention is a compound of Formula II, wherein n is 1 , 2 or 3.
  • the quinuclidine derivative of the invention is a compound of Formula II, wherein X represents a linker selected from -O-, -O-CH2-, -O-CH 2 -CH 2 -, -S-, and -CH 2 -.
  • the quinuclidine derivative of the invention is a compound of Formula II, wherein Y represents O, S, SO 2 , or NR', wherein R' represents hydrogen or alkyl.
  • the quinuclidine derivative of the invention of Formula II is
  • the quinuclidine derivative of the invention is a compound of Formula III wherein represents an optional double bond; n is 1 , 2 or 3; X represents a linker selected from -O-, -0-CH 2 -, -O-CH 2 -CH 2 -, -S-, -SO-,
  • B represents a monocyclic or polycyclic, carbocyclic or heterocyclic group, optionally substituted one or more times with substituents selected from the group consisting of alkyl, cycloalkyl, cycloalkyl-alkyl, alkoxy, hydroxyalkoxy, alkoxy-alkyl, alkoxy-alkoxy, cycloalkoxy, cycloalkoxy-alkyl, cycloalkoxy-alkoxy, halo, CF 3 , CN, NO 2 ,
  • NH 2 carboxy, carbamoyl, amido, sulfamoyl, and phenyl, or with another monocyclic or polycyclic, carbocyclic or heterocyclic group, which additional monocyclic or polycyclic, carbocyclic or heterocyclic group may optionally be substituted one or more times with substituents selected from the group consisting of alkyl, cycloalkyl, cycloalkyl-alkyl, alkoxy, hydroxyalkoxy, alkoxy-alkyl, alkoxy-alkoxy, cycloalkoxy, cycloalkoxy-alkyl, cycloalkoxy-alkoxy, halo, CF 3 , CN, NO2, NH 2 , carboxy, carbamoyl, amido, sulfamoyl, and phenyl.
  • the quinuclidine derivative of the invention is a compound of Formula III, wherein represents a single (covalent) bond.
  • the quinuclidine derivative of the invention is a compound of Formula III, wherein n is 1 , 2 or 3.
  • the quinuclidine derivative of the invention is a compound of Formula III, wherein X represents a linker selected from -0-, -O-CH2-. -O-CH 2 -CH 2 -, -S-, and -CH 2 -.
  • the quinuclidine derivative of the invention is a compound of Formula III, wherein B represents a monocyclic or polycyclic, carbocyclic or heterocyclic group, optionally substituted one or more times with substituents selected from the group consisting of alkyl, cycloalkyl, cycloalkyl- alkyl, alkoxy, hydroxyalkoxy, alkoxy-alkyl, alkoxy-alkoxy, cycloalkoxy, cycloalkoxy-alkyl, cycloalkoxy-alkoxy, halo, CF 3 , CN, N0 , NH 2 , carboxy, carbamoyl, amido, sulfamoyl, and phenyl, or with another monocyclic or polycyclic, carbocyclic or heterocyclic group, which additional monocyclic or polycyclic, carbocyclic or heterocyclic group may optionally be substituted one or more times with substituents selected from the group consisting of alkyl, cycl
  • the quinuclidine derivative of the invention is a compound of Formula III, wherein B represents a phenyl group, which phenyl is optionally substituted one or two times with substituents selected from the group consisting of alkyl, cycloalkyl, alkoxy, cycloalkoxy, halo, CF 3 , CN, NO 2 - NH 2 , and phenyl.
  • the quinuclidine derivative of the invention of Formula III is ( ⁇ )-3-(2-Phenyl-imidazo[1 ,2-b]pyridazin-6-yloxy)-1-azabicyclo[2.2.2]octane; or an enantiomer thereof, or a pharmaceutically-acceptable addition salt thereof, or an onium salt thereof.
  • halo represents fluoro, chloro, bromo or iodo.
  • a trihalomethyl group represents e.g. a trifluoromethyl group, a trichloromethyl group, and similar trihalo-substituted methyl groups.
  • an alkyl group designates a univalent saturated, straight or branched hydrocarbon chain.
  • the hydrocarbon chain preferably contain of from one to eighteen carbon atoms (C-i-is-alkyl), more preferred of from one to six carbon atoms (C- ⁇ - 6 -alkyl; lower alkyl), including pentyl, isopentyl, neopentyl, tertiary pentyl, hexyl and isohexyl.
  • alkyl represents a C1- 4 - alkyl group, including butyl, isobutyl, secondary butyl, and tertiary butyl.
  • alkyl represents a C ⁇ - 3 -alkyl group, which may in particular be methyl, ethyl, propyl or isopropyl.
  • a cycloalkyl group designates a cyclic alkyl group, preferably containing of from three to seven carbon atoms (C 3 - -cycloalkyl), including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • a cycloalkyl-alkyl group designates a cycloalkyl group as defined above, which cycloalkyl group is substituted on an alkyl group as also defined above.
  • Examples of preferred cycloalkyl-alkyl groups of the invention include cyclopropylmethyl and cyclopropylethyl.
  • an alkoxy group designates an "alkyl-O-" group, wherein alkyl is as defined above. Examples of preferred alkoxy groups of the invention include methoxy and ethoxy.
  • a hydroxy-alkoxy group designates an alkoxy group as defined above, which alkoxy group is substituted with one or more hydroxy groups.
  • Preferred hydroxy-alkoxy groups of the invention include 2-hydroxy-ethoxy, 3- hydroxy-propoxy, 4-hydroxy-butoxy, 5-hydroxy-pentoxy and 6-hydroxy-hexoxy.
  • a cycloalkoxy group designates a "cycloalkyl- O-" group, wherein cycloalkyl is as defined above.
  • an alkoxy-alkyl group designates an "alkyl-O- alkyl-” group, wherein alkyl is as defined above.
  • Examples of preferred alkoxy-alkyl groups of the invention include methoxy-methyl, methoxy-ethyl, ethoxy-methyl, and ethoxy-ethyl.
  • alkoxy-alkoxy group designates an "alkyl- O-alkyl-O-" group, wherein alkyl is as defined above.
  • alkoxy- alkoxy groups of the invention include methoxy-methoxy, methoxy-ethoxy, ethoxy- methoxy, and ethoxy-ethoxy.
  • a cycloalkoxy-alkyl group designates a "cycloalkyl-O-alkyl" group, wherein cycloalkyl and alkyl are as defined above.
  • a cycloalkoxy-alkoxy group designates a
  • cycloalkyl-O-alkyl-O- group, wherein cycloalkyl and alkyl are as defined above.
  • a mono- or polycyclic carbocyclic group is a mono- or polycyclic carbocyclic group holding carbon only as ring atom.
  • the ring structure may in particular be aromatic (i.e. an aryl group), or saturated or partially saturated.
  • Preferred mono- or polycyclic carbocyclic groups of the invention include phenyl; indanyl, in particular 4-indanyl and 5-indanyl; indenyl, in particular 1-indenyl, 2-indenyl and 3-indenyl; naphthyl, in particular 1 -naphthyl and 2-naphthyl; 5,6,7,8- tetrahydro-naphthyl, in particular 5,6,7,8-tetrahydro-1-naphthyl and 5,6,7,8- tetrahydro-2-naphthyl; azulenyl, in particular 1 -azulenyl, 2-azulenyl and 3-azulenyl; fluorenyl, in particular 1-fluorenyl, 2-fluorenyl, 3-fluorenyl and 4-fluorenyl; and anthracenyl, in particular 1 -anthracenyl and 2-an
  • the mono- or polycyclic carbocyclic group may in particular be an aromatic group (aryl).
  • aryl groups of the invention include phenyl; indenyl, in particular 1-indenyl, 2-indenyl and 3-indenyl; naphthyl, in particular 1 -naphthyl and
  • azulenyl in particular 1 -azulenyl, 2-azulenyl and 3-azulenyl
  • anthracenyl in particular 1 -anthracenyl and 2-anthracenyl.
  • a mono- or polycyclic heterocyclic group is a mono- or polycyclic compound, which holds one or more heteroatoms in its ring structure.
  • poly-heterocyclic groups includes benzo-fused five- and six- membered heterocyclic rings containing one or more heteroatoms.
  • Preferred heteroatoms include nitrogen (N), oxygen (O), and sulphur (S).
  • One or more of the ring structures may in particular be aromatic (i.e. a heteroaryl).
  • Preferred monocyclic heterocyclic groups of the invention include pyridyl, in particular pyrid-2-yl, pyrid-3-yl and pyrid-4-yl; thienyl, in particular thien-2-yl and thien-3-yl; furanyl, in particular furan-2-yl and furan-3-yl; pyridazinyl, in particular pyridazin-3-yl and pyridazin-4-yl; thiazolyl, in particular thiazol-2-yl, thiazol-4-yl and thiazol-5-yl; and thiadiazolyl, in particular 1 ,3,4-thiadiazol-2-yl, 1 ,3,4-thiadiazol-5-yl, 1 ,2,4-thiadiazol-3-yl and 1 ,2,4-thiadiazol-5-yl.
  • Preferred polycyclic heterocyclic of the invention include indolyl, in particular indol-2-yl and indol-3-yl; isoindolyl, in particular isoindol-2-yl; quinolinyl, in particular quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl and quinolin-6-yl; quinoxalinyl, in particular quinoxalin-2-yl and quinoxalin-3-yl; benzimidazolyl, in particular benzimidazol-2-yl; benzoxazolyl, in particular benzoxazol-2-yl; benzthiazolyl, in particular benzthiazoI-2-yl; benzisothiazolyl, in particular benzisothiazol-3-yl; benztriazolyl, in particular 1,2,3-benztriazol-1-yl; imidazo[1 ,2-b]pyridaziny
  • the quinuclidine derivative of the invention may be provided in any form suitable for the intended administration. Suitable forms include pharmaceutically (i.e. physiologically) acceptable salts, and pre- or prodrug forms of the quinuclidine derivative of the invention.
  • pharmaceutically acceptable addition salts include, without limitation, the non-toxic inorganic and organic acid addition salts such as the hydrochloride derived from hydrochloric acid, the hydrobromide derived from hydrobromic acid, the nitrate derived from nitric acid, the perchlorate derived from perchloric acid, the phosphate derived from phosphoric acid, the sulphate derived from sulphuric acid, the formate derived from formic acid, the acetate derived from acetic acid, the aconate derived from aconitic acid, the ascorbate derived from ascorbic acid, the benzenesulphonate derived from benzensulphonic acid, the benzoate derived from benzoic acid,
  • oxalic acid which may not be considered pharmaceutically acceptable, may be useful in the preparation of salts useful as intermediates in obtaining a chemical compound of the invention and its pharmaceutically acceptable acid addition salt.
  • pharmaceutically acceptable cationic salts of a chemical compound of the invention include, without limitation, the sodium, the potassium, the calcium, the magnesium, the zinc, the aluminium, the lithium, the choline, the lysine, and the ammonium salt, and the like, of a chemical compound of the invention containing an anionic group.
  • Such cationic salts may be formed by procedures well known and described in the art.
  • the "onium salts" of N-containing compounds are also contemplated as pharmaceutically acceptable salts (aza-onium salts).
  • Preferred aza-onium salts include the alkyl-onium salts, in particular the methyl- and the ethyl-onium salts; the cycloalkyl-onium salts, in particular the cyclopropyl-onium salts; and the cycloalkylalkyl-onium salts, in particular the cyclopropyl-methyl-onium salts.
  • the quinuclidine derivatives of the present invention may exist in (+) and (-) forms as well as in racemic forms ( ⁇ ).
  • the racemates of these isomers and the individual isomers themselves are within the scope of the present invention.
  • Racemic forms can be resolved into the optical antipodes by known methods and techniques.
  • One way of separating the diastereomeric salts is by use of an optically active acid, and liberating the optically active amine compound by treatment with a base.
  • Another method for resolving racemates into the optical antipodes is based upon chromatography on an optical active matrix.
  • Racemic compounds of the present invention can thus be resolved into their optical antipodes, e.g., by fractional crystallisation of d- or I- (tartrates, mandelates, or camphorsulphonate) salts for example.
  • the quinuclidine derivatives of the present invention may also be resolved by the formation of diastereomeric amides by reaction of the chemical compounds of the present invention with an optically active activated carboxylic acid such as that derived from (+) or (-) phenylalanine, (+) or (-) phenylglycine, (+) or (-) camphanic acid or by the formation of diastereomeric carbamates by reaction of the chemical compound of the present invention with an optically active chloroformate or the like.
  • an optically active activated carboxylic acid such as that derived from (+) or (-) phenylalanine, (+) or (-) phenylglycine, (+) or (-) camphanic acid
  • Optical active compounds can also be prepared from optical active starting materials.
  • the quinuclidine derivatives of the invention may be prepared by conventional methods for chemical synthesis, e.g. those described in the working examples.
  • the starting materials for the processes described in the present application are known or may readily be prepared by conventional methods from commercially available chemicals.
  • one compound of the invention can be converted to another compound of the invention using conventional methods.
  • the end products of the reactions described herein may be isolated by conventional techniques, e.g. by extraction, crystallisation, distillation, chromatography, etc.
  • the present invention relates to novel quinuclidine derivatives, which are found to be cholinergic ligands at the nicotinic acetylcholine receptors (nAChR), and modulators of the monoamine receptors, in particular the biogenic amine transporters such as the serotonin receptor (5-HTR), the dopamine receptor (DAR) and the norepinephrine receptor (NER), and of the biogenic amine transporters for serotonin (5-HT), dopamine (DA) and norepinephrine (NE).
  • the biogenic amine transporters such as the serotonin receptor (5-HTR), the dopamine receptor (DAR) and the norepinephrine receptor (NER), and of the biogenic amine transporters for serotonin (5-HT), dopamine (DA) and norepinephrine (NE).
  • the compounds of the present invention may in particular be agonists, partial agonists, antagonists and allosteric modulators of the receptor.
  • the quinuclidine derivatives of the invention may be useful for the treatment of diseases or conditions as diverse as CNS related diseases, PNS related diseases, diseases related to smooth muscle contraction, endocrine disorders, diseases related to neuro-degeneration, diseases related to inflammation, pain, and withdrawal symptoms caused by the termination of abuse of chemical substances.
  • the quinuclidine derivatives of the invention are used for the treatment of diseases, disorders, or conditions relating to the central nervous system.
  • diseases or disorders includes anxiety, cognitive disorders, learning deficit, memory deficits and dysfunction, Alzheimer's disease, attention deficit, attention deficit hyperactivity disorder (ADHD), Parkinson's disease, Huntington's disease, Amyotrophic Lateral Sclerosis, Gilles de la Tourette's syndrome, psychosis, depression, mania, manic depression, schizophrenia, obsessive compulsive disorders (OCD), panic disorders, eating disorders such as anorexia nervosa, bulimia and obesity, narcolepsy, nociception, AIDS-dementia, senile dementia, periferic neuropathy, autism, dyslexia, tardive dyskinesia, hyperkinesia, epilepsy, bulimia, post- traumatic syndrome, social phobia, sleeping disorders, pseudodementia, Ganser's syndrome, pre-menstrual syndrome, late luteal
  • diseases, disorders, or conditions relating to the central nervous system for which the quinuclidine derivatives of the invention are used are cognitive disorders, psychosis, schizophrenia and/or depression.
  • the quinuclidine derivatives of the invention may be useful for the treatment of diseases, disorders, or conditions associated with smooth muscle contractions, including convulsive disorders, angina pectoris, premature labour, convulsions, diarrhoea, asthma, epilepsy, tardive dyskinesia, hyperkinesia, premature ejaculation, and erectile difficulty.
  • the quinuclidine derivatives of the invention may be useful for the treatment of endocrine disorders, such as thyrotoxicosis, pheochromocytoma, hypertension and arrhythmias.
  • the quinuclidine derivatives of the invention may be useful for the treatment of neurodegenerative disorders, including transient anoxia and induced neurodegeneration.
  • the quinuclidine derivatives of the invention may be useful for the treatment of inflammatory diseases, disorders, or conditions, including inflammatory skin disorders such as acne and rosacea, Chron's disease, inflammatory bowel disease, ulcerative colitis, and diarrhoea.
  • the quinuclidine derivatives of the invention may be useful for the treatment of mild, moderate or even severe pain of acute, chronic or recurrent character, as well as pain caused by migraine, postoperative pain, and phantom limb pain.
  • the pain may in particular be neuropathic pain, chronic headache, central pain, pain related to diabetic neuropathy, to post therapeutic neuralgia, or to peripheral nerve injury.
  • the quinuclidine derivatives of the invention may be useful for the treatment of withdrawal symptoms caused by termination of use of addictive substances.
  • addictive substances include nicotine containing products such as tobacco, opioids such as heroin, cocaine and morphine, benzodiazepines and benzodiazepine-like drugs, and alcohol.
  • Withdrawal from addictive substances is in general a traumatic experience characterised by anxiety and frustration, anger, anxiety, difficulties in concentrating, restlessness, decreased heart rate and increased appetite and weight gain.
  • treatment covers treatment, prevention, prophylactics and alleviation of withdrawal symptoms and abstinence as well as treatment resulting in a voluntary diminished intake of the addictive substance.
  • the quinuclidine derivatives of the invention are used as diagnostic agents, e.g. for the identification and localisation of nicotinic receptors in various tissues.
  • the invention provides novel pharmaceutical compositions comprising a therapeutically effective amount of the quinuclidine derivatives of the invention.
  • a chemical compound of the invention for use in therapy may be administered in the form of the raw chemical compound, it is preferred to introduce the active ingredient, optionally in the form of a physiologically acceptable salt, in a pharmaceutical composition together with one or more adjuvants, excipients, carriers, buffers, diluents, and/or other customary pharmaceutical auxiliaries.
  • the invention provides pharmaceutical compositions comprising the quinuclidine derivative together with one or more pharmaceutically acceptable carriers therefore, and, optionally, other therapeutic and/or prophylactic ingredients, know and used in the art.
  • the carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the recipient thereof.
  • the pharmaceutical composition of the invention may be administered by any convenient route, which suits the desired therapy.
  • Preferred routes of administration include oral administration, in particular in tablet, in capsule, in drage, in powder, or in liquid form, and parenteral administration, in particular cutaneous, subcutaneous, intramuscular, or intravenous injection.
  • the pharmaceutical composition of the invention can be manufactured by a person skilled in the art by use of standard methods and conventional techniques appropriate to the desired formulation. When desired, compositions adapted to give sustained release of the active ingredient may be employed. Further details on techniques for formulation and administration may be found in the latest edition of Remington's Pharmaceutical Sciences (Maack Publishing Co., Easton, PA).
  • compositions containing of from about 0.1 to about 500 mg of active ingredient per individual dose, preferably of from about 1 to about 100 mg, most preferred of from about 1 to about 10 mg, are suitable for therapeutic treatments.
  • the active ingredient may be administered in one or several doses per day.
  • a satisfactory result can, in certain instances, be obtained at a dosage as low as 0.1 ⁇ g/kg i.v. and 1 ⁇ g/kg p.o.
  • the upper limit of the dosage range is presently considered to be about 10 mg/kg i.v. and 100 mg/kg p.o.
  • Preferred ranges are from about 0.1 ⁇ g/kg to about 10 mg/kg/day i.v., and from about 1 ⁇ g/kg to about 100 mg/kg/day p.o.
  • the compounds of the invention may be useful for the treatment of diseases or conditions as diverse as CNS related diseases, PNS related diseases, diseases related to smooth muscle contraction, endocrine disorders, diseases related to neuro-degeneration, diseases related to inflammation, pain, and withdrawal symptoms caused by the termination of abuse of chemical substances.
  • the invention provides methods of the treatment, prevention or alleviation of diseases or disorders or conditions of a living animal body, including a human, which disease or disorder is responsive to the action of a monoamine receptor modulator, and which method comprises the step of administering to such a living animal body, including a human, in need thereof a therapeutically effective amount of the quinuclidine derivative of the invention.
  • treating covers treatment, prevention, prophylaxis or alleviation
  • disease covers illnesses, diseases, disorders and conditions related to the disease in question.
  • a suitable dosage lies within the range of from about 0.1 to about 500 milligram of active substance daily, more preferred of from about 10 to about 70 milligram of active substance daily, administered once or twice a day, dependent as usual upon the exact mode of administration, form in which administered, the indication toward which the administration is directed, the subject involved and the body weight of the subject involved, and further the preference and experience of the physician or veterinarian in charge.
  • the compound may also be named ( ⁇ )-3-(biphenyl-4-yl-methoxy)- quinuclidine.
  • the corresponding fumaric acid salt was obtained by addition of a diethyl ether and methanol mixture (9:1) saturated with fumaric acid. Mp 131.3-133.8°C.
  • the compound also may be named ( ⁇ )-3-(Dibenzofuran-2-yloxy)- quinuclidine.
  • ⁇ -Bungarotoxine is a peptide isolated from the venom of the Elapidae snake Bungarus multicinctus. It has high affinity for neuronal and neuromuscular nicotinic receptors, where it acts as a potent antagonist.
  • Preparations are performed at 0-4°C. Cerebral cortices from male Wistar rats (150-250 g) are homogenised for 10 seconds in 15 ml of 20 mM Hepes buffer containing 118 mM NaCI, 4.8 mM KCI, 1.2 mM MgSO 4 and 2.5 mM CaCI 2 (pH 7.5) using an Ultra-Turrax homogeniser. The tissue suspension is subjected to centrifugation at 27,000 x g for 10 minutes.
  • the supernatant is discarded and the pellet is washed twice by centrifugation at 27,000 x g for 10 minutes in 20 ml of fresh buffer, and the final pellet is then re-suspended in fresh buffer containing 0.01 % BSA (35 ml per g of original tissue) and used for binding assays.
  • the amount of radioactivity on the filters is determined by conventional liquid scintillation counting. Specific binding is total binding minus non-specific binding.
  • the test value is given as an IC 50 (the concentration of the test substance which inhibits the specific binding of ⁇ -obungarotoxin by 50%).

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Endocrinology (AREA)
  • Reproductive Health (AREA)
  • Diabetes (AREA)
  • Cardiology (AREA)
  • Gynecology & Obstetrics (AREA)
  • Psychiatry (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Pulmonology (AREA)
  • Psychology (AREA)
  • Pregnancy & Childbirth (AREA)
  • Pain & Pain Management (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Hospice & Palliative Care (AREA)
  • Urology & Nephrology (AREA)
  • Child & Adolescent Psychology (AREA)
  • Vascular Medicine (AREA)
  • Dermatology (AREA)
  • Nutrition Science (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
PCT/DK2003/000538 2002-08-14 2003-08-13 Novel quinuclidine derivatives and their use Ceased WO2004016608A1 (en)

Priority Applications (20)

Application Number Priority Date Filing Date Title
UAA200500621A UA78812C2 (en) 2002-08-14 2003-08-13 Quinuclidine derivatives and their use
NZ538058A NZ538058A (en) 2002-08-14 2003-08-13 Quinuclidine derivatives and their use for treating disorders related to CNS and PNS
CA002493245A CA2493245A1 (en) 2002-08-14 2003-08-13 Novel quinuclidine derivatives and their use
EP03787742A EP1532144B1 (en) 2002-08-14 2003-08-13 quinuclidine derivatives and their use
HK06100949.6A HK1080860B (en) 2002-08-14 2003-08-13 Novel quinuclidine derivatives and their use
BR0313153-0A BR0313153A (pt) 2002-08-14 2003-08-13 Derivado de quinuclidina, composição farmacêutica, uso de um derivado de quinuclidina, e, método de tratamento, prevenção ou alìvio de uma doença ou um distúrbio ou uma condição de um corpo animal vivo
AU2003250322A AU2003250322B2 (en) 2002-08-14 2003-08-13 Novel quinuclidine derivatives and their use
DE60318860T DE60318860T2 (de) 2002-08-14 2003-08-13 Chinucledin - derivate und deren verwendung
JP2005502013A JP2005538187A (ja) 2002-08-14 2003-08-13 新規キヌクリジン誘導体及びその使用方法
US10/522,150 US20050245567A1 (en) 2002-08-14 2003-08-13 Novel quinuclidine derivatives and their use
MXPA05001702A MXPA05001702A (es) 2002-08-14 2003-08-13 Derivados de quinuclidina novedosos y su uso.
AT04741916T ATE496050T1 (de) 2003-08-13 2004-06-29 Neue chinuklidinderivative und deren pharmazeutische verwendung
DE602004031124T DE602004031124D1 (de) 2003-08-13 2004-06-29 Neue chinuklidinderivative und deren pharmazeutische verwendung
PCT/EP2004/051283 WO2005016923A1 (en) 2003-08-13 2004-06-29 Novel quinuclidine derivatives and their pharmaceutical use
US10/568,148 US7750022B2 (en) 2003-08-13 2004-06-29 Quinuclidine derivatives and their pharmaceutical use
EP04741916A EP1656375B1 (en) 2003-08-13 2004-06-29 Novel quinuclidine derivatives and their pharmaceutical use
IL16625405A IL166254A0 (en) 2002-08-14 2005-01-12 Novel quinuclidine derivatives and their use
NO20051264A NO20051264L (no) 2002-08-14 2005-03-11 Nye kinuklidinderivater og deres anvendelse
IS7742A IS7742A (is) 2002-08-14 2005-03-14 Nýjar kvínúklidín-afleiður og notkun þeirra
US12/206,302 US20090005390A1 (en) 2002-08-14 2008-09-08 Novel quinuclidine derivatives and their use

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
DKPA200201208 2002-08-14
DKPA200201208 2002-08-14
DKPA200201472 2002-10-02
DKPA200201472 2002-10-02

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US12/206,302 Division US20090005390A1 (en) 2002-08-14 2008-09-08 Novel quinuclidine derivatives and their use

Publications (1)

Publication Number Publication Date
WO2004016608A1 true WO2004016608A1 (en) 2004-02-26

Family

ID=31889349

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/DK2003/000538 Ceased WO2004016608A1 (en) 2002-08-14 2003-08-13 Novel quinuclidine derivatives and their use

Country Status (18)

Country Link
US (2) US20050245567A1 (enExample)
EP (2) EP1905771A3 (enExample)
JP (1) JP2005538187A (enExample)
KR (1) KR20050055711A (enExample)
CN (1) CN100513406C (enExample)
AT (1) ATE384720T1 (enExample)
AU (1) AU2003250322B2 (enExample)
BR (1) BR0313153A (enExample)
CA (1) CA2493245A1 (enExample)
DE (1) DE60318860T2 (enExample)
IL (1) IL166254A0 (enExample)
IS (1) IS7742A (enExample)
MX (1) MXPA05001702A (enExample)
NO (1) NO20051264L (enExample)
NZ (1) NZ538058A (enExample)
PL (1) PL375533A1 (enExample)
RU (1) RU2323217C2 (enExample)
WO (1) WO2004016608A1 (enExample)

Cited By (37)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6262265A (ja) * 1985-09-13 1987-03-18 Hitachi Ltd 復水器自動検査補修システム
WO2005016923A1 (en) * 2003-08-13 2005-02-24 Neurosearch A/S Novel quinuclidine derivatives and their pharmaceutical use
WO2005066167A3 (en) * 2003-12-22 2005-09-01 Abbott Lab 3-quinuclidinyl heteroatom bridged biaryl derivatives
WO2005066166A3 (en) * 2003-12-22 2005-09-01 Abbott Lab 3-quinuclidinyl amino-substituted biaryl derivatives
WO2005100351A1 (en) * 2004-04-14 2005-10-27 Astrazeneca Ab NOVEL 2-(1-AZA-BICYCLO[2.2.2]OCT-3-yl)-2,3-DIHYDROISOINDOL-l-ONE/5,6-DIHYDRO-FURO[2,3-c]PYRROL-4ONE DERIVATIVES LIGANDS FOR ALPHA 7 NICOTINIC ACETYLCHOLINE RECEPTOR
WO2005077899A3 (en) * 2004-02-04 2005-12-01 Abbott Lab Amino-substituted tricyclic derivatives and methods of use
WO2006005608A1 (en) * 2004-07-14 2006-01-19 Novartis Ag 3-(heteroaryl-oxy)-2-alkyl-1-aza-bicycloalkyl derivatives as alpha.7-nachr ligands for the treatment of cns diseases
WO2006065233A1 (en) * 2004-12-10 2006-06-22 Abbott Laboratories Fused bicycloheterocycle substituted quinuclidine derivatives
US7094572B2 (en) 2003-03-14 2006-08-22 Bristol-Myers Squibb Polynucleotide encoding a novel human G-protein coupled receptor variant of HM74, HGPRBMY74
US7160876B2 (en) 2003-12-22 2007-01-09 Abbott Laboratories Fused bicycloheterocycle substituted quinuclidine derivatives
WO2007045478A1 (en) * 2005-10-21 2007-04-26 Novartis Ag Novel 1-aza bicycloalkyl derivatives for the treatment of psychotic and neurodegenerative disorders
WO2007068476A1 (en) * 2005-12-16 2007-06-21 Novartis Ag [ (1h- indol- 5 -yl) -heteroaryloxy] - (1-aza-bicyclo [3.3.1] nonanes as cholinergic ligands of the n-achr for the treatment of psychotic and neurodegenrative disorders.
WO2007068475A1 (en) * 2005-12-16 2007-06-21 Novartis Ag (1-aza-bicyclo[3.3.1] n0n-4-yl)-[5-(ih-indol-5-yl)-heteroaryl]-amines as cholinergic ligands of the n-achr for the treatment of psychotic and neurodegenerative disorders
US7241773B2 (en) 2003-12-22 2007-07-10 Abbott Laboratories 3-quinuclidinyl heteroatom bridged biaryl derivatives
US7309699B2 (en) 2003-12-22 2007-12-18 Abbott Laboratories 3-Quinuclidinyl amino-substituted biaryl derivatives
FR2904002A1 (fr) * 2006-07-19 2008-01-25 Galderma Res & Dev S N C Snc Modulateurs de la lanosterol synthetase dans le traitement de l'acne ou de l'hyperseborrhee
US7365193B2 (en) 2004-02-04 2008-04-29 Abbott Laboratories Amino-substituted tricyclic derivatives and methods of use
JP2008525464A (ja) * 2004-12-22 2008-07-17 メモリー・ファーマシューティカルズ・コーポレイション α−７ニコチン性受容体リガンド並びにその製造及び使用
JP2008546700A (ja) * 2005-06-15 2008-12-25 アボット・ラボラトリーズ 縮合ビシクロ複素環置換キヌクリジン誘導体
JP2009509964A (ja) * 2005-09-23 2009-03-12 メモリー・ファーマシューティカルズ・コーポレイション インダゾール類、ベンゾチアゾール類、ベンゾイソオキサゾール類、ピラゾロピリジン類、イソチアゾロピリジン類、およびそれらの製造と用途
JP2009143956A (ja) * 2002-09-04 2009-07-02 Novartis Ag アザビシクロアルキルエーテルおよびそのα７−ＮＡＣＨＲアゴニストとしての使用
EP2135609A1 (en) 2004-11-05 2009-12-23 Novartis AG Combinations of nicotinic acetylcholine alpha 7 receptor agonists
US7655657B2 (en) 2003-12-22 2010-02-02 Abbott Laboratories Fused bicycloheterocycle substituted quinuclidine derivatives
EP2409703A1 (en) 2007-08-02 2012-01-25 Targacept, Inc. Treatment with alpha7-selective ligands
KR101174173B1 (ko) 2004-06-18 2012-08-14 노파르티스 아게 1-아자-비시클로〔3.3.1〕노난
US8314119B2 (en) 2006-11-06 2012-11-20 Abbvie Inc. Azaadamantane derivatives and methods of use
JP2012533601A (ja) * 2009-07-23 2012-12-27 ノバルティス アーゲー 運動失調症の処置または予防のための、アザビシクロアルキル誘導体またはピロリジン−２−オン誘導体の使用
US8383657B2 (en) 2007-12-21 2013-02-26 Abbott Laboratories Thiazolylidine urea and amide derivatives and methods of use thereof
US8476296B2 (en) 2009-01-26 2013-07-02 Targacept, Inc. Preparation and therapeutic applications of (2S,3R)-N-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]OCT-3-yl)-3,5-difluorobenzamide
WO2014111751A1 (en) * 2013-01-15 2014-07-24 Novartis Ag Use of alpha 7 nicotinic receptor agonists for the treatment of narcolepsy
WO2014111837A1 (en) * 2013-01-15 2014-07-24 Novartis Ag Use of alpha 7 nicotinic acetylcholine receptor agonists
US8884017B2 (en) 2001-12-27 2014-11-11 Bayer Intellectual Property Gmbh 2-heteroarylcarboxylic acid amides
US9108961B2 (en) 2010-05-17 2015-08-18 Forum Pharmaceuticals, Inc. Crystalline form of (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide hydrochloride
US9464078B2 (en) 2010-09-23 2016-10-11 Abbvie Inc. Monohydrate of azaadamantane derivatives
US9585877B2 (en) 2012-05-08 2017-03-07 Forum Pharmaceuticals, Inc. Methods of maintaining, treating or improving cognitive function
US10537539B2 (en) 2009-09-22 2020-01-21 Novartis Ag Use of nicotinic acetylcholine receptor alpha 7 activators
US11311525B2 (en) 2013-01-15 2022-04-26 Novartis Ag Use of alpha 7 nicotinic acetylcholine receptor agonists

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120220729A1 (en) * 2011-02-28 2012-08-30 Boehringer Ingelheim International Gmbh Liquid phase separation of plasmid dna isoforms and topoisomers
WO2016100184A1 (en) 2014-12-16 2016-06-23 Forum Pharmaceuticals, Inc. Geminal substituted quinuclidine amide compounds as agonists of alpha-7 nicotinic acetylcholine receptors
WO2016201096A1 (en) 2015-06-10 2016-12-15 Forum Pharmaceuticals, Inc. Aminobenzisoxazole compounds as agonists of a7-nicotinic acetylcholine receptors
WO2017027600A1 (en) 2015-08-12 2017-02-16 Forum Pharmaceuticals, Inc. GEMINAL SUBSTITUTED AMINOBENZISOXAZOLE COMPOUNDS AS AGONISTS OF α7-NICOTINIC ACETYLCHOLINE RECEPTORS

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH08134067A (ja) * 1994-11-11 1996-05-28 Yamanouchi Pharmaceut Co Ltd キヌクリジン誘導体
US5589477A (en) * 1990-08-31 1996-12-31 Nippon Shinyaku Company, Limited Pyrimidine derivatives and drugs
US5646289A (en) * 1994-10-24 1997-07-08 Eli Lilly And Company Heterocyclic compounds and their preparation and use
WO1998015551A1 (fr) * 1996-10-08 1998-04-16 Synthelabo Derives de quinuclidine en tant qu'antagonistes des recepteurs muscariniques
US5763457A (en) * 1995-11-13 1998-06-09 Eli Lilly And Company Method for treating anxiety
WO1998027983A1 (en) * 1996-12-20 1998-07-02 Novo Nordisk A/S A method of treating hypercholesterolemia and related disorders
US5852037A (en) * 1995-11-13 1998-12-22 Eli Lilly And Company Method for treating anxiety
WO1999031097A1 (fr) * 1997-12-12 1999-06-24 Sanofi-Synthelabo Derives d'imidazole en tant qu'antagonistes des recepteurs muscariniques m3
US5998404A (en) * 1994-10-24 1999-12-07 Eli Lilly And Company Heterocyclic compounds and their use

Family Cites Families (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3534053A (en) * 1967-05-24 1970-10-13 American Home Prod Quinuclidine derivatives
SU495310A1 (ru) * 1974-03-05 1975-12-15 Всесоюзный Научно-Исследовательский Химико-Фармацевтический Институт Им.С.Орджоникидзе Хинуклидил-3-диарал(гетерил) карбинолы, про вл ющие антигистаминную, антисеротониновую и антиаллергическую активность и способ их получени
DE3718317A1 (de) * 1986-12-10 1988-06-16 Bayer Ag Substituierte basische 2-aminotetraline
CA1307790C (en) * 1987-08-04 1992-09-22 Ian Anthony Cliffe Ethers
US5405853A (en) * 1987-09-10 1995-04-11 Merck Sharpe & Dohme Ltd. Thiadiazoles useful in the treatment of senile dementia
JP2752143B2 (ja) * 1988-04-01 1998-05-18 三共株式会社 カルバペネム誘導体
EP0363085A3 (en) * 1988-10-03 1991-03-27 Beecham Group Plc Novel compounds
IT1227729B (it) * 1988-12-23 1991-05-06 Savio Spa Procedimento e dispositivo per la rimozione delle fibre deteriorate durante il riattacco del filo in un filatoio open-end
YU84791A (sh) * 1990-05-19 1994-06-10 Boehringer Ingelheim Kg. Biciklicni 1-aza-cikloalkalni
ZA92278B (en) * 1991-02-01 1992-10-28 Akzo Nv 3-quinuclidine derivatives
GB9201749D0 (en) * 1992-01-28 1992-03-11 Smithkline Beecham Plc Medicaments
US5948793A (en) * 1992-10-09 1999-09-07 Abbott Laboratories 3-pyridyloxymethyl heterocyclic ether compounds useful in controlling neurotransmitter release
WO1995030675A1 (en) * 1994-05-06 1995-11-16 Smithkline Beecham Plc Biphenylcarboxamides useful as 5-ht1d antagonists
JPH0840999A (ja) * 1994-08-04 1996-02-13 Yamanouchi Pharmaceut Co Ltd フルオロインダン誘導体
US5512574A (en) * 1994-12-21 1996-04-30 American Home Products Corporation Quinuclidine and azabicyclo 2.2.1! heptane pyrazinyl ethers as muscarinic agonists
JP2000500452A (ja) * 1995-11-13 2000-01-18 イーライ・リリー・アンド・カンパニー 不安の処置法
HN1998000118A (es) * 1997-08-27 1999-02-09 Pfizer Prod Inc 2 - aminopiridinas que contienen sustituyentes de anillos condensados.
WO1999042461A1 (en) * 1998-02-23 1999-08-26 Warner-Lambert Company Substituted quinoxaline derivatives as interleukin-8 receptor antagonists
JP4616971B2 (ja) * 2000-07-18 2011-01-19 田辺三菱製薬株式会社 １−アザビシクロアルカン化合物およびその医薬用途
ATE385497T1 (de) * 2000-12-01 2008-02-15 Neurosearch As 3-substituierte quinuclidin-derivate und deren verwendung als nikotinischen agonisten

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5589477A (en) * 1990-08-31 1996-12-31 Nippon Shinyaku Company, Limited Pyrimidine derivatives and drugs
US5646289A (en) * 1994-10-24 1997-07-08 Eli Lilly And Company Heterocyclic compounds and their preparation and use
US5998404A (en) * 1994-10-24 1999-12-07 Eli Lilly And Company Heterocyclic compounds and their use
JPH08134067A (ja) * 1994-11-11 1996-05-28 Yamanouchi Pharmaceut Co Ltd キヌクリジン誘導体
US5763457A (en) * 1995-11-13 1998-06-09 Eli Lilly And Company Method for treating anxiety
US5852037A (en) * 1995-11-13 1998-12-22 Eli Lilly And Company Method for treating anxiety
WO1998015551A1 (fr) * 1996-10-08 1998-04-16 Synthelabo Derives de quinuclidine en tant qu'antagonistes des recepteurs muscariniques
WO1998027983A1 (en) * 1996-12-20 1998-07-02 Novo Nordisk A/S A method of treating hypercholesterolemia and related disorders
WO1999031097A1 (fr) * 1997-12-12 1999-06-24 Sanofi-Synthelabo Derives d'imidazole en tant qu'antagonistes des recepteurs muscariniques m3

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE STN INTERNATIONAL File ZCAPLUS, ZCAPLUS accession no. 1996:509522, Document no. 125:167796; YAMANOUCHI PHARMA CO LTD: "Preparation of quinuclidine derivatives as squalene synthase inhibitors", XP002261104 *

Cited By (88)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6262265A (ja) * 1985-09-13 1987-03-18 Hitachi Ltd 復水器自動検査補修システム
US8884017B2 (en) 2001-12-27 2014-11-11 Bayer Intellectual Property Gmbh 2-heteroarylcarboxylic acid amides
US8236803B2 (en) 2002-09-04 2012-08-07 Novartis Ag Aza-bicycloalkyl ethers and their use as alpha7-nAChR agonists
EP2308876A1 (en) * 2002-09-04 2011-04-13 Novartis AG Aza-bicycloalkyl ethers and their use as alpha7-nAChR agonists
EP2100893A1 (en) * 2002-09-04 2009-09-16 Novartis Ag Aza-bicycloalkyl ethers and their use as alpha7-nachr agonists
US7579362B2 (en) 2002-09-04 2009-08-25 Novartis Ag Aza-bicycloalkyl ethers and their use as alpha7-nAChR agonists
JP2009143956A (ja) * 2002-09-04 2009-07-02 Novartis Ag アザビシクロアルキルエーテルおよびそのα７−ＮＡＣＨＲアゴニストとしての使用
US9849117B2 (en) 2002-09-04 2017-12-26 Novartis Ag Aza-bicycloalkyl ethers and their use as alpha7-nachr agonists
US7371822B2 (en) 2003-03-14 2008-05-13 Bristol-Myers Squibb Company Human G-protein coupled receptor variant of HM74, HGPRBMY74
US7094572B2 (en) 2003-03-14 2006-08-22 Bristol-Myers Squibb Polynucleotide encoding a novel human G-protein coupled receptor variant of HM74, HGPRBMY74
WO2005016923A1 (en) * 2003-08-13 2005-02-24 Neurosearch A/S Novel quinuclidine derivatives and their pharmaceutical use
US7750022B2 (en) 2003-08-13 2010-07-06 Neurosearch A/S Quinuclidine derivatives and their pharmaceutical use
US7655657B2 (en) 2003-12-22 2010-02-02 Abbott Laboratories Fused bicycloheterocycle substituted quinuclidine derivatives
US7674794B2 (en) 2003-12-22 2010-03-09 Abbott Laboratories Fused bicycloheterocycle substituted quinuclidine derivatives
US7309699B2 (en) 2003-12-22 2007-12-18 Abbott Laboratories 3-Quinuclidinyl amino-substituted biaryl derivatives
WO2005066167A3 (en) * 2003-12-22 2005-09-01 Abbott Lab 3-quinuclidinyl heteroatom bridged biaryl derivatives
US7241773B2 (en) 2003-12-22 2007-07-10 Abbott Laboratories 3-quinuclidinyl heteroatom bridged biaryl derivatives
US7160876B2 (en) 2003-12-22 2007-01-09 Abbott Laboratories Fused bicycloheterocycle substituted quinuclidine derivatives
EP2308875A1 (en) * 2003-12-22 2011-04-13 Abbott Laboratories Fused bicycloheterocycle substituted quinuclidine derivatives as .alpha.7 nAChR modulators
WO2005066166A3 (en) * 2003-12-22 2005-09-01 Abbott Lab 3-quinuclidinyl amino-substituted biaryl derivatives
WO2005077899A3 (en) * 2004-02-04 2005-12-01 Abbott Lab Amino-substituted tricyclic derivatives and methods of use
US7365193B2 (en) 2004-02-04 2008-04-29 Abbott Laboratories Amino-substituted tricyclic derivatives and methods of use
US7951791B2 (en) 2004-02-04 2011-05-31 Abbott Laboratories Amino-substituted tricyclic derivatives and methods of use
EP2258682A3 (en) * 2004-02-04 2011-03-09 Abbott Laboratories Amino-substituted tricyclic derivatives and methods of use
AU2005233492B2 (en) * 2004-04-14 2009-06-11 Astrazeneca Ab Novel 2-(1-aza-bicyclo[2.2.2]oct-3-yl)-2,3-dihydroisoindol-l-one/5,6-dihydro-furo[2,3-c]pyrrol-4one derivatives ligands for alpha 7 nicotinic acetylcholine receptor
US7566727B2 (en) 2004-04-14 2009-07-28 Astrazeneca Ab 2-(1-aza-bicyclo[2.2.2]oct-3-yl)-2,3-dihydro-isoindole-1-one/5,6-dihydro-furo[2,3-c] pyrrol-4-one derivative ligands for alpha 7 nicotinic acetylcholine receptor
WO2005100351A1 (en) * 2004-04-14 2005-10-27 Astrazeneca Ab NOVEL 2-(1-AZA-BICYCLO[2.2.2]OCT-3-yl)-2,3-DIHYDROISOINDOL-l-ONE/5,6-DIHYDRO-FURO[2,3-c]PYRROL-4ONE DERIVATIVES LIGANDS FOR ALPHA 7 NICOTINIC ACETYLCHOLINE RECEPTOR
RU2372350C2 (ru) * 2004-04-14 2009-11-10 Астразенека Аб НОВЫЕ ПРОИЗВОДНЫЕ 2-(1-АЗА-БИЦИКЛО[2.2.2]ОКТ-3-ИЛ)-2,3-ДИГИДРОИЗОИНДОЛ-1-ОНА/5,6-ДИГИДРО-ФУРО[2,3-c]ПИРРОЛ-4-ОНА В КАЧЕСТВЕ ЛИГАНДОВ К АЛЬФА 7 НИКОТИНОВОМУ АЦЕТИЛХОЛИНОВОМУ РЕЦЕПТОРУ
JP2007532637A (ja) * 2004-04-14 2007-11-15 アストラゼネカ・アクチエボラーグ α７ニコチン性アセチルコリン受容体に対する新規な２−（１−アザ−ビシクロ［２．２．２］オクタ−３−イル）−２，３−ジヒドロイソインドール−１−オン／５，６−ジヒドロ−フロ［２，３−ｃ］ピロール−４−オン誘導体リガンド
US8933090B2 (en) 2004-06-18 2015-01-13 Novartis Ag 1-aza-bicyclo[3.3.1]nonanes
US9475811B2 (en) 2004-06-18 2016-10-25 Novartis Ag 1-aza-bicyclo[3.3.1]nonanes
KR101174173B1 (ko) 2004-06-18 2012-08-14 노파르티스 아게 1-아자-비시클로〔3.3.1〕노난
US8609662B2 (en) 2004-07-14 2013-12-17 Novartis Ag 3-(heteroaryl-oxy)-2-alkyl-1-aza-bicycloalkyl derivatives as alpha. 7-nachr ligands for the treatment of CNS diseases
RU2402551C2 (ru) * 2004-07-14 2010-10-27 Новартис Аг 3-(ГЕТЕРОАРИЛОКСИ)-2-АЛКИЛ-1-АЗАБИЦИКЛОАЛКИЛЬНЫЕ ПРОИЗВОДНЫЕ, КАК ЛИГАНДЫ АЛЬФА-7-nAChR (НИКОТИНОВЫХ АЦЕТИЛХОЛИНОВЫХ РЕЦЕПТОРОВ), ПРЕДНАЗНАЧЕННЫЕ ДЛЯ ЛЕЧЕНИЯ ЗАБОЛЕВАНИЙ ЦЕНТРАЛЬНОЙ НЕРВНОЙ СИСТЕМЫ
NO338622B1 (no) * 2004-07-14 2016-09-19 Novartis Ag 3-(heteroaryl-oksy)-2-alkyl-1-aza-bicykloalkylderivater som alfa-7-nAChR ligander for terapi av CNS-sykdommer
AU2005261866B8 (en) * 2004-07-14 2010-04-08 Novartis Ag 3-(heteroaryl-oxy)-2-alkyl-1-aza-bicycloalkyl derivatives as alpha.7-NACHR ligands for the treatment of CNS diseases
AU2005261866B2 (en) * 2004-07-14 2009-12-10 Novartis Ag 3-(heteroaryl-oxy)-2-alkyl-1-aza-bicycloalkyl derivatives as alpha.7-NACHR ligands for the treatment of CNS diseases
WO2006005608A1 (en) * 2004-07-14 2006-01-19 Novartis Ag 3-(heteroaryl-oxy)-2-alkyl-1-aza-bicycloalkyl derivatives as alpha.7-nachr ligands for the treatment of cns diseases
JP2008506646A (ja) * 2004-07-14 2008-03-06 ノバルティス アクチエンゲゼルシャフト ＣＮＳ疾患を処置するためのα７ｎＡＣｈＲリガンドとしての３−（ヘテロアリール−オキシ）−２−アルキル−１−アザ−ビシクロアルキル誘導体
EP2457911A1 (en) * 2004-07-14 2012-05-30 Novartis AG 3-(heteroaryl-oxy)-2-alkyl-1-aza-bicycloalkyl derivatives as alpha.7-nAChR ligands for the treatment of CNS diseases.
CN103554101B (zh) * 2004-07-14 2016-05-11 诺瓦提斯公司 用于治疗cns疾病的3-(杂芳基-氧基)-2-烷基-1-氮杂-二环烷基衍生物
US9657010B2 (en) 2004-07-14 2017-05-23 Novartis Ag Substituted quinuclidines as alpha 7-nicotinic acetylcholine receptor activity modulators
EP2332537A1 (en) 2004-11-05 2011-06-15 Novartis AG Combinations of nicotinic acetylcholine alpha 7 receptor agonists
EP2135609A1 (en) 2004-11-05 2009-12-23 Novartis AG Combinations of nicotinic acetylcholine alpha 7 receptor agonists
JP2008523058A (ja) * 2004-12-10 2008-07-03 アボット・ラボラトリーズ 縮合ビシクロ複素環置換キヌクリジン誘導体
WO2006065233A1 (en) * 2004-12-10 2006-06-22 Abbott Laboratories Fused bicycloheterocycle substituted quinuclidine derivatives
JP2008525464A (ja) * 2004-12-22 2008-07-17 メモリー・ファーマシューティカルズ・コーポレイション α−７ニコチン性受容体リガンド並びにその製造及び使用
JP2008546700A (ja) * 2005-06-15 2008-12-25 アボット・ラボラトリーズ 縮合ビシクロ複素環置換キヌクリジン誘導体
JP2009509964A (ja) * 2005-09-23 2009-03-12 メモリー・ファーマシューティカルズ・コーポレイション インダゾール類、ベンゾチアゾール類、ベンゾイソオキサゾール類、ピラゾロピリジン類、イソチアゾロピリジン類、およびそれらの製造と用途
US8173667B2 (en) 2005-10-21 2012-05-08 Novartis Ag 1-aza-bicycloalkyl derivatives
WO2007045478A1 (en) * 2005-10-21 2007-04-26 Novartis Ag Novel 1-aza bicycloalkyl derivatives for the treatment of psychotic and neurodegenerative disorders
AU2006303453B2 (en) * 2005-10-21 2011-07-14 Novartis Ag Novel 1-aza bicycloalkyl derivatives for the treatment of psychotic and neurodegenerative disorders
RU2471797C2 (ru) * 2005-12-16 2013-01-10 Новартис Аг [(1н-индол-5-ил)-гетероарилокси]-1-(азабицикло[3.3.1]нонаны, как холинергические лиганды n-achr, предназначенные для лечения психотических и нейродегенеративных нарушений
WO2007068475A1 (en) * 2005-12-16 2007-06-21 Novartis Ag (1-aza-bicyclo[3.3.1] n0n-4-yl)-[5-(ih-indol-5-yl)-heteroaryl]-amines as cholinergic ligands of the n-achr for the treatment of psychotic and neurodegenerative disorders
AU2006326257B2 (en) * 2005-12-16 2011-06-16 Novartis Ag (1-aza-bicyclo[3.3.1] non-4-yl)-[5-(1H-indol-5-yl)-heteroaryl]-amines as cholinergic ligands of the n-AChR for the treatment of psychotic and neurodegenerative disorders
EP2361914A1 (en) * 2005-12-16 2011-08-31 Novartis AG [(1h-indol-5-yl)-heteroaryloxy]-(1-aza-bicyclo[3.3.1]nonanes as cholinergic ligands of the n-achr for the treatment of psychotic and neurodegenrative disorders.
CN101305003B (zh) * 2005-12-16 2011-06-08 诺瓦提斯公司 用于治疗精神病和神经变性疾病的作为nAChR胆碱能配体的(1-氮杂-双环[3.3.1]壬-4-基)-[5-(1H-吲哚-5-基)-杂芳基)-胺
KR101174943B1 (ko) * 2005-12-16 2012-08-17 노파르티스 아게 정신병성 및 신경퇴행성 장애의 치료를 위한 ｎ-ａｃｈｒ의 콜린성 리간드로서의 〔(1ｈ-인돌-5-일)-헤테로아릴옥시〕-(1-아자-비시클로〔3.3.1〕노난
EP2354141A1 (en) * 2005-12-16 2011-08-10 Novartis AG (1-aza-bicyclo[3.3.1]non-4-yl)-[5-(1h-indol-5-yl)-heteroaryl]-amines as cholinergic ligands of the n-achr for the treatment of psychotic and neurodegenrative disorders.
US8048885B2 (en) 2005-12-16 2011-11-01 Novartis Ag Organic compounds
US9206181B2 (en) 2005-12-16 2015-12-08 Novartis Ag 1-aza-bicyclo[3.3.1] non-4-yl)-[5-(1H-indol-5-yl)-heteroaryl]-amines as cholinergic ligands of the n-AChR for the treatment of psychotic and neurodegenerative disorders
US7713976B2 (en) 2005-12-16 2010-05-11 Novartis Ag [(1H-indol-5-yl)-heteroaryloxy]-1-aza-bicylco[3.3.1]nonanes as cholinergic ligands of the n-AChR for the treatment of psychotic and neurodegenerative disorders
WO2007068476A1 (en) * 2005-12-16 2007-06-21 Novartis Ag [ (1h- indol- 5 -yl) -heteroaryloxy] - (1-aza-bicyclo [3.3.1] nonanes as cholinergic ligands of the n-achr for the treatment of psychotic and neurodegenrative disorders.
US7713977B2 (en) 2005-12-16 2010-05-11 Novartis Ag (1-aza-bicyclo[3.3.1]non-4-yl)-[5-(1H-indol-5-yl)-heteroaryl]-amines as cholinergic ligands of the n-achr for the treatment of psychotic and neurodegenerative disorders
TWI423965B (zh) * 2005-12-16 2014-01-21 Novartis Ag 用於治療精神病和神經退化性疾病之［（１ｈ－吲哚－５－基）雜芳］－１－氮雜雙環［３.３.１］壬烷作為ｎ－ａｃｈｒ膽鹼能配體
FR2904002A1 (fr) * 2006-07-19 2008-01-25 Galderma Res & Dev S N C Snc Modulateurs de la lanosterol synthetase dans le traitement de l'acne ou de l'hyperseborrhee
WO2008009852A3 (fr) * 2006-07-19 2009-03-19 Galderma Res & Dev Modulateurs de la lanostérol synthétase dans le traitement de l'acné ou de l'hyperséborrhée
US8314119B2 (en) 2006-11-06 2012-11-20 Abbvie Inc. Azaadamantane derivatives and methods of use
US8987453B2 (en) 2006-11-06 2015-03-24 Abbvie Inc. Azaadamantane derivatives and methods of use
EP2409703A1 (en) 2007-08-02 2012-01-25 Targacept, Inc. Treatment with alpha7-selective ligands
EP2484363A1 (en) 2007-08-02 2012-08-08 Targacept, Inc. (2S,3R)-N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-5-methylthiophene-2-carboxamide
US8383657B2 (en) 2007-12-21 2013-02-26 Abbott Laboratories Thiazolylidine urea and amide derivatives and methods of use thereof
US8901151B2 (en) 2009-01-26 2014-12-02 Targacept, Inc. Preparation and therapeutic applications of (2S, 3R)-N-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]OCT-3-yl)-3,5-difluorobenzamide
US8476296B2 (en) 2009-01-26 2013-07-02 Targacept, Inc. Preparation and therapeutic applications of (2S,3R)-N-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]OCT-3-yl)-3,5-difluorobenzamide
US9173876B2 (en) 2009-01-26 2015-11-03 Targacept, Inc. Preparation and therapeutic applications of (2S,3R)-N-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-3,5-difluorobenzamide
JP2012533601A (ja) * 2009-07-23 2012-12-27 ノバルティス アーゲー 運動失調症の処置または予防のための、アザビシクロアルキル誘導体またはピロリジン−２−オン誘導体の使用
US11096916B2 (en) 2009-09-22 2021-08-24 Novartis Ag Use of nicotinic acetylcholine receptor alpha 7 activators
US10537539B2 (en) 2009-09-22 2020-01-21 Novartis Ag Use of nicotinic acetylcholine receptor alpha 7 activators
US9108961B2 (en) 2010-05-17 2015-08-18 Forum Pharmaceuticals, Inc. Crystalline form of (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide hydrochloride
US9550767B2 (en) 2010-05-17 2017-01-24 Forum Pharmaceuticals, Inc. Crystalline form of (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide hydrochloride monohydrate
US9273044B2 (en) 2010-05-17 2016-03-01 Forum Pharmaceuticals, Inc. Crystalline form of (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide hydrochloride monohydrate
US9464078B2 (en) 2010-09-23 2016-10-11 Abbvie Inc. Monohydrate of azaadamantane derivatives
US9585877B2 (en) 2012-05-08 2017-03-07 Forum Pharmaceuticals, Inc. Methods of maintaining, treating or improving cognitive function
WO2014111751A1 (en) * 2013-01-15 2014-07-24 Novartis Ag Use of alpha 7 nicotinic receptor agonists for the treatment of narcolepsy
WO2014111837A1 (en) * 2013-01-15 2014-07-24 Novartis Ag Use of alpha 7 nicotinic acetylcholine receptor agonists
JP2018021042A (ja) * 2013-01-15 2018-02-08 ノバルティス アーゲー アルファ７ニコチン性アセチルコリン受容体アゴニストの使用
JP2016508159A (ja) * 2013-01-15 2016-03-17 ノバルティス アーゲー アルファ７ニコチン性アセチルコリン受容体アゴニストの使用
US11311525B2 (en) 2013-01-15 2022-04-26 Novartis Ag Use of alpha 7 nicotinic acetylcholine receptor agonists

Also Published As

Publication number Publication date
EP1532144B1 (en) 2008-01-23
RU2323217C2 (ru) 2008-04-27
MXPA05001702A (es) 2005-04-19
CN100513406C (zh) 2009-07-15
DE60318860T2 (de) 2008-05-21
RU2005101748A (ru) 2006-01-20
IL166254A0 (en) 2006-01-15
US20050245567A1 (en) 2005-11-03
JP2005538187A (ja) 2005-12-15
EP1532144A1 (en) 2005-05-25
AU2003250322B2 (en) 2010-01-21
DE60318860D1 (de) 2008-03-13
BR0313153A (pt) 2005-06-28
US20090005390A1 (en) 2009-01-01
CN1675205A (zh) 2005-09-28
IS7742A (is) 2005-03-14
EP1905771A2 (en) 2008-04-02
AU2003250322A1 (en) 2004-03-03
PL375533A1 (en) 2005-11-28
CA2493245A1 (en) 2004-02-26
NZ538058A (en) 2006-11-30
HK1080860A1 (zh) 2006-05-04
KR20050055711A (ko) 2005-06-13
ATE384720T1 (de) 2008-02-15
NO20051264L (no) 2005-05-18
EP1905771A3 (en) 2008-11-26

Similar Documents

Publication Publication Date Title
AU2003250322B2 (en) Novel quinuclidine derivatives and their use
US7750011B2 (en) Diazabicyclic aryl derivatives and their medical use
EP1562945A1 (en) 1,4-diazabicyclo(3,2,2)nonane derivatives, preparation and therapeutical use thereof
US7674899B2 (en) Dimeric azacyclic compounds and their use
US7652010B2 (en) Azabicyclic aryl derivatives and their medical use
US7514450B2 (en) Azabicyclic aryl derivatives
US7223753B2 (en) Diazabicyclic biaryl derivatives
US7750022B2 (en) Quinuclidine derivatives and their pharmaceutical use
US7612074B2 (en) Diazabicyclic aryl derivatives as cholinergy ligands
HK1080860B (en) Novel quinuclidine derivatives and their use
NZ553277A (en) Novel azabicyclic aryl derivatives and their medical use
UA78812C2 (en) Quinuclidine derivatives and their use

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 2003787742

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 166254

Country of ref document: IL

WWE Wipo information: entry into national phase

Ref document number: 2003250322

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 2493245

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 10522150

Country of ref document: US

WWE Wipo information: entry into national phase

Ref document number: 2005/00735

Country of ref document: ZA

Ref document number: 200500735

Country of ref document: ZA

WWE Wipo information: entry into national phase

Ref document number: 538058

Country of ref document: NZ

WWE Wipo information: entry into national phase

Ref document number: 20038190788

Country of ref document: CN

WWE Wipo information: entry into national phase

Ref document number: 2005502013

Country of ref document: JP

WWE Wipo information: entry into national phase

Ref document number: PA/a/2005/001702

Country of ref document: MX

WWE Wipo information: entry into national phase

Ref document number: 1020057002514

Country of ref document: KR

Ref document number: 375533

Country of ref document: PL

Ref document number: 175/CHENP/2005

Country of ref document: IN

ENP Entry into the national phase

Ref document number: 2005101748

Country of ref document: RU

Kind code of ref document: A

WWP Wipo information: published in national office

Ref document number: 2003787742

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 1020057002514

Country of ref document: KR

WWG Wipo information: grant in national office

Ref document number: 2003787742

Country of ref document: EP