WO2009071577A1 - Dérivés d'oxadiazole et leur utilisation comme modulateurs des récepteurs nicotiniques de l'acétylcholine - Google Patents

Dérivés d'oxadiazole et leur utilisation comme modulateurs des récepteurs nicotiniques de l'acétylcholine Download PDF

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WO2009071577A1
WO2009071577A1 PCT/EP2008/066699 EP2008066699W WO2009071577A1 WO 2009071577 A1 WO2009071577 A1 WO 2009071577A1 EP 2008066699 W EP2008066699 W EP 2008066699W WO 2009071577 A1 WO2009071577 A1 WO 2009071577A1
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unsubstituted
substituted
methyl
compound
phenyl
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PCT/EP2008/066699
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David Nigel Hurst
Nigel Paul King
Sing Yeung Mak
Tiziana Scoccitti
John Skidmore
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Glaxo Group Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
    • C07D271/113—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to novel oxadiazole derivatives having pharmacological activity, processes for their preparation, compositions containing them and their use in the treatment of neurological, psychiatric disorders and gastrointestinal disorders.
  • Nicotinic acetylcholine receptors are cation-specific, excitatory ligand-gated ion channels that are widely expressed throughout the central and peripheral nervous systems.
  • 16 mammalian nAChR subunit genes have been cloned: 5 encoding muscle receptor subunits, and 11 encoding neuronal receptor subunits.
  • the nicotinic ⁇ 7 receptor subunit is predominantly expressed in the mammalian central nervous system (CNS), where it is thought to assemble as a functional homopentameric complex, and is also expressed in peripheral tissues including the sympathetic nervous system, immune cells and the Gl tract.
  • CNS mammalian central nervous system
  • Activation of neuronal nicotinic ⁇ 7 receptors by selective agonists or the endogenous ligand acetylcholine can modulate the release of various neurotransmitters including glutamate, GABA, dopamine, and noradrenaline and, thus, has the potential to modulate a range of neurological functions. Additionally, in vivo studies have shown that ⁇ 7 nAChR agonists can modulate neurotransmitter release in brain areas such as the cortex and hippocampus that are relevant to cognition (Paterson D et al, (2000) Prog Neurobiol 61 :75-111.
  • ⁇ 7 nAChR agonists e.g. GTS-21 (3-(2,4-dimethoxybenzylidene)anabaseine), AR-R 17779 ((- ⁇ spiro ⁇ -azabicyclo ⁇ octane-S. ⁇ '-oxazoldin ⁇ '-oneH-propyl-benzylidene anabaseine) and SSR-180771 (4-bromophenyl 1 ,4-diazabicyclo[3.2.2]nonane-4-carboxylate hydrochloride) in rodent and primate cognition models including the radial arm maze (Levin E. D. et al.
  • ⁇ 7 nAChRs Activation of ⁇ 7 nAChRs has also been reported to ameliorate sensory gating deficits in both preclinical (Simosky J. K. et al., (2001 ) Biological Psychiatry. 50(7):493-500) and small clinical studies. These data suggest that novel ⁇ 7 nAChR agonists and/or partial agonists such as the current series could be useful for the treatment of cognitive impairments in neurological and psychiatric disorders such as Alzheimer's disease, related neurodegenerative disorders and schizophrenia.
  • the present invention provides, in a first aspect, compounds of formula (I) or a salt thereof:
  • R 1 and R 2 independently represent hydrogen, Ci -6 alkyl or C 3-6 cycloalkyl; or R 1 and R 2 together with the nitrogen atom to which they are attached form a nitrogen containing heterocyclyl group which is unsubstituted or substituted with 1 , 2, or 3 substituents selected from methyl or fluoro;
  • Q represents -(CH 2 ) n - wherein n represents 3 or 4;
  • A is selected from a 9 to 10 membered fused bicyclic ring system containing 0, 1 , 2 or 3 heteroatoms selected from O, N and S with a maximum of 2 heteroatoms present in the same ring, which fused bicyclic ring system which can be unsubstituted or substituted with 1 , 2 or 3 substituents independently selected from C 1-6 alkyl, C 1-6 alkoxy, halo, phenyl or if at least two substituents are present two of the substitutents can together form a third ring, and 9/-/- ⁇ -carbolinyl.
  • the compounds of the invention are compounds of formula (I) or a salt thereof:
  • R 1 and R 2 independently represent hydrogen, Ci -6 alkyl or C 3-6 cycloalkyl; or R 1 and R 2 together with the nitrogen atom to which they are attached form a nitrogen containing heterocyclyl group which is unsubstituted or substituted with 1 , 2, or 3 substituents selected from methyl or fluoro;
  • Q represents -(CH 2 ) n - wherein n represents 3 or 4;
  • A represents a 9 to 10 membered fused bicyclic ring system containing 0, 1 , 2 or 3 heteroatoms selected from O, N and S with a maximum of 2 heteroatoms present in the same ring, which fused bicyclic ring system which can be unsubstituted or substituted with 1 , 2 or 3 substituents independently selected from C 1-6 alkyl, C 1-6 alkoxy, halo, phenyl or if at least two substituents are present two of the substitutents can together form a third ring.
  • 'C 1-6 alkyl' refers to a linear or branched saturated hydrocarbon group containing from 1 to 6 carbon atoms.
  • examples of such groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or hexyl and the like.
  • the terms propyl, butyl etc include all straight and branched chain forms having the appropriate number of carbon atoms e.g. propyl includes n-propyl and isopropyl.
  • 'C 1-6 alkoxy' refers to an -0-C 1-6 alkyl group wherein C 1-6 alkyl is as defined herein. Examples of such groups include methoxy, ethoxy, propoxy, butoxy, pentoxy or hexoxy and the like. As for alkyl unless a particular stucture is specified the terms propoxy, butoxy etc include all straight and branched chain forms having the appropriate number of carbon atoms e.g. propoxy includes n-propoxy and isopropoxy.
  • 'halo' refers to a fluorine, chlorine, bromine or iodine atom.
  • C 3-6 cycloalkyl' refers to a saturated monocyclic hydrocarbon ring of 3 to 6 carbon atoms.
  • C 3-6 cycloalkyl groups thus include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • nitrogen containing heterocyclyl group includes a 4-7 membered monocyclic saturated or partially unsaturated aliphatic ring system, a 6-9 membered saturated or partially unsaturated bridged ring system or a 4-7 membered saturated or partially unsaturated aliphatic ring fused to a benzene ring containing a nitrogen atom in addition to 1 or 2 optional additional heteroatoms selected from oxygen, nitrogen or sulphur.
  • Suitable examples of such monocyclic rings include pyrrolidinyl, azetidinyl, piperidinyl, piperazinyl, morpholinyl, hexahydroazepanyl, hexahydrodiazepanyl and homomorpholinyl.
  • bridged ring systems are azabicycloheptanyl and azabicyclononanyl.
  • Suitable examples of benzofused heterocyclic rings include indolinyl, isoindolinyl, 2,3,4,5-tetrahydro- 1H-3-benzazepinyl or tetrahydroisoquinolinyl.
  • 9 to 10 membered fused bicyclic ring system includes but is not limited to the following ring systems indolinyl, indolyl, isoindolinyl, isoindolyl, indenyl, benzofuranyl, benzothienyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzoxazinyl, benzopyranyl, benzothiopyranyl, quinolinyl, isoquinolinyl, chromenyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, furopyridinyl, naphthyl, dihydrobenzoxazinyl, dihydrochromenyl, dihydrobenzodioxinyl, tetrahydroquinolinyl, tetrahydroquinoxalinyl, tetrahydronaphthaleny
  • fused bicyclic ring system includes but is not limited to the following ring systems thienofuranyl, indolizinyl, indolinyl, isoindolinyl, benzofuranyl, benzothienyl, indazolyl, benzimidazolyl, benzothiazolyl, imidazopyridinyl, benzoxazolyl, quinolinyl, quinolizinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl and naphthyl.
  • fused bicyclic ring system can be bonded to the oxadiazole core through either ring in the ring system.
  • A represents a 9 to 10 membered fused bicyclic ring system containing 0, 1 or 2 heteroatoms selected from O, N and S.
  • Q represents -(CH 2 ) n - wherein n is 4. In another embodiment, Q represents -(CH 2 ) n - wherein n is 3.
  • R 1 and R 2 together with the nitrogen atom which they are attached form a nitrogen containing heterocyclyl group e.g. piperidinyl, morpholinyl, pyrrolidinyl wherein the heterocyclyl group is unsubstituted or substituted with 1 , 2, or 3 substituents selected from methyl or fluoro.
  • a nitrogen containing heterocyclyl group e.g. piperidinyl, morpholinyl, pyrrolidinyl wherein the heterocyclyl group is unsubstituted or substituted with 1 , 2, or 3 substituents selected from methyl or fluoro.
  • R 1 and R 2 together with the nitrogen atom which they are attached form a nitrogen containing heterocyclyl group e.g. piperidinyl, morpholinyl, pyrrolidinyl wherein the heterocyclyl group is unsubstituted.
  • a nitrogen containing heterocyclyl group e.g. piperidinyl, morpholinyl, pyrrolidinyl wherein the heterocyclyl group is unsubstituted.
  • R 1 and R 2 together with the nitrogen atom to which they are attached form a 4-7 membered monocyclic saturated or partially unsaturated aliphatic ring system containing a nitrogen atom in addition to 1 or 2 optional additional heteroatoms selected from oxygen, nitrogen or sulphur, and which monocyclic ring system is unsubstituted.
  • A is selected from indolinyl, benzofuranyl, benzothienyl, benzothiazolyl, imidazopyridinyl, benzimidazolyl, benzoxazolyl and quinolinyl.
  • A is substituted by at least two substituents and two substituents form a third ring this may be a C5-6 carbocyclic or 5-6 membered heterocyclic ring, e.g. pyrrolidinyl or piperidinyl.
  • the substituents are independently selected from Ci-6 alkyl, Ci -6 alkoxy, halo and phenyl.
  • A may be selected from indolinyl, benzofuranyl, benzothienyl, benzothiazolyl, imidazopyridinyl, benzimidazolyl, benzoxazolyl and quinolinyl and A is bonded to the oxadiazole core through the phenyl ring of the bicyclic ring system.
  • A is selected from indolinyl, benzofuranyl, quinolinyl and benzothienyl and A is bonded to the oxadiazole core through the ring containing the heteroatom.
  • A represents a 9 to 10 membered fused bicyclic ring system selected from indolyl, benzothiazolyl, imidazopyridinyl, benzothienyl, benzofuranyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl and py rrolopy rid i ny I , each of which 9 to 10 membered fused bicyclic ring system can be unsubstituted or substituted with 1 , 2 or 3 substituents independently selected from Ci -6 alkyl, Ci -6 alkoxy, halo and phenyl.
  • A is selected from
  • A is selected from
  • - pyrrolopyridinyl which is unsubstituted or substituted with 1 substituent selected from methyl.
  • benzothiazolyl is unsubstituted or substituted with 1 substituent selected from methyl.
  • A is selected from
  • benzothiazol-2-yl is unsubstituted or substituted with 1 substituent selected from methyl.
  • A is indol-5-yl which is substituted with 1or 2 substituents selected from phenyl and methyl or unsubstituted indol-3-yl.
  • A represents a 9 to 10 membered fused bicyclic ring system containing 0, 1 or 2 heteroatoms selected from O, N and S, which is substituted with at least two substituents which form a third ring, said third ring is selected from C5-6 carbocyclic or 5-6 membered heterocyclic ring, e.g. pyrrolidinyl or piperidinyl.
  • A is unsubstituted dihydro-pyrrolo-[1 ,2-a]-benzimidazolyl.
  • A is unsubstituted 9H- ⁇ -carbolinyl.
  • A represents a 9 to 10 membered fused bicyclic ring system selected from indolyl, benzothiazolyl, imidazopyridinyl, benzothienyl, benzofuranyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl and pyrrolopyridinyl, each of which fused bicyclic ring system can be unsubstituted or substituted with 1 , 2 or 3 substituents independently selected from C 1-6 alkyl, C 1-6 alkoxy, halo and phenyl, and Q represents - (CH 2 ) n - wherein n represents 3 or 4, and R 1 and R 2 together with the nitrogen atom to which they are attached form a 4-7 membered monocyclic saturated or partially unsaturated aliphatic ring system containing a nitrogen atom in addition to 1 or 2 optional additional heteroatoms selected from oxygen, nitrogen or sulphur, e.g.
  • A is selected from
  • Q represents -(CH 2 ) n - wherein n represents 3 or 4, and R 1 and R 2 together with the nitrogen atom to which they are attached form a 4-7 membered monocyclic saturated or partially unsaturated aliphatic ring system containing a nitrogen atom in addition to 1 or 2 optional additional heteroatoms selected from oxygen, nitrogen or sulphur, e.g. piperidinyl, morpholinyl, pyrrolidinyl wherein the monocyclyl ring is unsubstituted or substituted with 1 , 2, or 3 substituents selected from methyl or fluoro, particularly the monocyclic ring is unsubstituted.
  • A is selected from
  • - pyrrolopyridinyl which is unsubstituted or substituted with 1 substituent selected from methyl; and wherein Q represents -(CH 2 ) n - wherein n represents 3 or 4, and R 1 and R 2 together with the nitrogen atom to which they are attached form a 4-7 membered monocyclic saturated or partially unsaturated aliphatic ring system containing a nitrogen atom in addition to 1 or 2 optional additional heteroatoms selected from oxygen, nitrogen or sulphur, e.g.
  • piperidinyl, morpholinyl, pyrrolidinyl wherein the monocyclyl ring is unsubstituted or substituted with 1 , 2, or 3 substituents selected from methyl or fluoro, particularly the monocyclic ring is unsubstituted.
  • benzothiazolyl is unsubstituted or substituted with 1 substituent selected from methyl.
  • A is selected from
  • A is indol-5-yl which is substituted with 1or 2 substituents selected from phenyl and methyl or unsubstituted indol-3-yl
  • Q represents -(CH 2 ) n - wherein n represents 4, and R 1 and R 2 together with the nitrogen atom which they are attached form a nitrogen containing heterocyclyl group selected from piperidinyl, morpholinyl and pyrrolidinyl wherein the heterocyclyl group is unsubstituted.
  • A represents a 9 to 10 membered fused bicyclic ring system containing 0, 1 or 2 heteroatoms selected from O, N and S, which is substituted with at least two substituents which form a third ring, said third ring is selected from C5-6 carbocyclic or 5-6 membered heterocyclic ring, e.g.
  • pyrrolidinyl or piperidinyl and Q represents -(CH 2 ) n - wherein n represents 3 or 4, and R 1 and R 2 together with the nitrogen atom to which they are attached form a 4-7 membered monocyclic saturated or partially unsaturated aliphatic ring system containing a nitrogen atom in addition to 1 or 2 optional additional heteroatoms selected from oxygen, nitrogen or sulphur, e.g. piperidinyl, morpholinyl, pyrrolidinyl wherein the monocyclyl ring is unsubstituted or substituted with 1 , 2, or 3 substituents selected from methyl or fluoro, particularly the monocyclic ring is unsubstituted.
  • the 4-7 membered monocyclic saturated or partially unsaturated aliphatic ring system containing a nitrogen atom is selected from piperidinyl, morpholinyl and pyrrolidinyl.
  • A is unsubstituted dihydro-pyrrolo-[1 ,2-a]-benzimidazolyl
  • Q represents -(CH 2 ) n - wherein n represents 4, and R 1 and R 2 together with the nitrogen atom to which they are attached form a 4-7 membered monocyclic saturated or partially unsaturated aliphatic ring system containing a nitrogen atom in addition to 1 or 2 optional additional heteroatoms selected from oxygen, nitrogen or sulphur, e.g.
  • A is unsubstituted 9H- ⁇ -carbolinyl
  • Q represents -(CH 2 ) n - wherein n represents 4, and R 1 and R 2 together with the nitrogen atom to which they are attached form a 4-7 membered monocyclic saturated or partially unsaturated aliphatic ring system containing a nitrogen atom in addition to 1 or 2 optional additional heteroatoms selected from oxygen, nitrogen or sulphur, e.g. piperidinyl, morpholinyl, pyrrolidinyl wherein the monocyclyl ring is unsubstituted or substituted with 1 , 2, or 3 substituents selected from methyl or fluoro, particularly the monocyclic ring is unsubstituted.
  • A is selected from indolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzamidazolyl and benzoxazolyl wherein A is unsubstituted or substituted with 1 to 3 substituents independently selected from Ci -6 alkyl, Ci -6 alkoxy, halo and phenyl, and A is bonded to the oxadiazole core through the phenyl ring of the bicyclic ring system, Q represents -(CH 2 ) n - wherein n represents 3 or 4, and R 1 and R 2 together with the nitrogen atom to which they are attached form a 4-7 membered monocyclic saturated or partially unsaturated aliphatic ring system containing a nitrogen atom in addition to 1 or 2 optional additional heteroatoms selected from oxygen, nitrogen or sulphur, e.g.
  • A is selected from indolyl, benzofuranyl, benzothiazolyl, quinolinyl, isoquinolinyl, imidazopyridinyl, pyrolopyridinyl and benzothienyl wherein A is unsubstituted or substituted with 1 to 3 substituents independently selected from Ci -6 alkyl, Ci -6 alkoxy, halo and phenyl, and A is bonded to the oxadiazole core through a ring containing a heteroatom, and Q represents -(CH 2 ) n - wherein n represents 3 or 4, and R 1 and R 2 together with the nitrogen atom which they are attached form a nitrogen containing heterocyclyl group e.g. piperidinyl, morpholinyl, pyrrolidinyl wherein the heterocyclyl group is unsubstituted.
  • Compounds of formula (I) and salts thereof include the compounds of Examples 1 to 38 and salts thereof.
  • a compound of formula (I) or a salt thereof is selected from a compound of Examples 1 , 2, 8, 22, 26 and 28, or a salt thereof.
  • the present invention encompasses all isomers of formula (I) and their salts including all geometric, tautomeric and optical forms, and mixtures thereof (e.g. racemic mixtures). Where additional chiral centres are present in compounds of formula (I), the present invention includes within its scope all possible diastereoisomers, including mixtures thereof.
  • the different isomeric forms may be separated or resolved one from the other by conventional methods, or any given isomer may be obtained by conventional synthetic methods or by stereospecific or asymmetric syntheses.
  • the present invention may also includes isotopically-labelled compounds, which are identical to the compounds of formula (I), except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 14 C, 18 F, 35 S, 123 I and 125 I.
  • Isotopically-labelled compounds of the present invention for example those into which radioactive isotopes such as 3 H and/or 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. 3 H and 14 C are considered useful due to their ease of preparation and detectability. 11 C and 18 F isotopes are considered useful in PET (positron emission tomography), and 125 I isotopes are considered useful in SPECT (single photon emission computerized tomography), all useful in brain imaging.
  • the compounds of formula (I) are not isotopically labelled.
  • Certain compounds of formula (I) may be prepared in crystalline or non-crystalline form, and may be optionally solvated, e.g. hydrated. Where solvates exist, this invention includes within its scope stoichiometric solvates as well as compounds containing variable amounts of solvate.
  • salts of compounds of formula (I) are preferably pharmaceutically acceptable.
  • Pharmaceutically acceptable salts include those described by Berge, Bighley and Monkhouse, J. Pharm. Sci., 1977, 66, 1-19.
  • pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable acids, including inorganic and organic acids.
  • Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, ethanedisulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, pamoic, pantothenic, phosphoric, propionic, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like. In some circumstances some salts may be non-stoichiometric.
  • the present invention also provides processes for the preparation of a compound of formula (I) or a salt thereof:
  • Step (a) typically comprises the use of a suitable reagent, such as 1 ,1- thiocarbonyldiimidazole or both carbon disulfide and a coupling agent such as dicyclohexylcarbodiimide in a suitable solvent such as ether, THF or DMF and at a suitable temperature such as room temperature.
  • a suitable reagent such as 1 ,1- thiocarbonyldiimidazole or both carbon disulfide and a coupling agent such as dicyclohexylcarbodiimide
  • a suitable solvent such as ether, THF or DMF
  • Step (b) typically comprises the reaction of a compound of formula (IV) with a compound of formula (III) in a suitable solvent such as DCM, DMF or THF at a suitable temperature such as 60 to 65°C.
  • Step (c) is a cyclisation reaction that typically comprises addition of a suitable reagent such as EDACHCI or dicyclohexylcarbodiimide to a compound of formula (II) in a suitable solvent such as DMF.
  • a suitable temperature for example, would be 60 to 80 0 C.
  • step (a) and/or step (b) can be carried out separately with isolation after step (a) and/or step (b) or carried out sequentially in a one pot reaction .
  • Step (a) typically comprises the use of a suitable reagent, such as hydrazine monohydrate in the presence of a suitable solvent, such as methanol at a suitable temperature, e.g. from room temperature to reflux.
  • a suitable solvent such as methanol
  • a suitable temperature e.g. from room temperature to reflux.
  • compounds of formula (Vl) are used as the methyl ester.
  • Step (b) typically comprises the reaction of a compound of formula (VIII) with BocNHNH 2 in a suitable solvent e.g. CH 2 CI 2 using a suitable coupling agent such as EDACHCI and optionally HOBt.
  • a suitable solvent e.g. CH 2 CI 2
  • a suitable coupling agent such as EDACHCI and optionally HOBt.
  • the reaction is typically conducted at room temperature.
  • Boc protecting group can be removed by conventional means, for example by treatment with HCI in dioxane.
  • Step (a) is a reaction of NHR I1 D R2 ; in the presence of a suitable base e.g. triethylamine in a suitable solvent such as ethanol at a suitable temperature, e.g. reflux.
  • a suitable base e.g. triethylamine
  • a suitable solvent such as ethanol
  • Step (b) typically comprises the use of MeNH 2 in a suitable solvent such as ethanol at a suitable temperature such as room temperature or the use of NH 2 NH 2 -H 2 O in a suitable solvent such as ethanol at a suitable temperature such as reflux.
  • R 1 , R 2 , and Q are as defined for compounds of formula (I) and t is 1 or 2.
  • Step (a) is a reaction of NHR 1 R 2 in the presence of a suitable reducing agent e.g. NaBH(OAc) 3 in a suitable solvent such as DCM at a suitable temperature, e.g. room temperature.
  • a suitable reducing agent e.g. NaBH(OAc) 3
  • a suitable solvent such as DCM
  • Step (b) typically comprises the use of MeNH 2 in a suitable solvent such as ethanol at a suitable temperature such as room temperature or the use of NH 2 NH 2 -H 2 O in a suitable solvent such as ethanol at a suitable temperature such as reflux.
  • Compounds of formula (I) may also be prepared by deprotecting a protected compound of formula (I). Examples of protecting groups and the means for their removal can be found in T. W. Greene 'Protective Groups in Organic Synthesis' (J. Wiley and Sons, 3 rd Ed. 1999). Suitable amine protecting groups include acyl (e.g. acetyl, removed by hydrolysis), carbonyls (e.g. 2',2',2'-trichloroethoxycarbonyl, removed with zinc in acetic acid, benzyloxycarbonyl, removed by acidolysis or hydrogenolysis or t-butoxycarbonyl, removed by acidolysis e.g.
  • acyl e.g. acetyl, removed by hydrolysis
  • carbonyls e.g. 2',2',2'-trichloroethoxycarbonyl, removed with zinc in acetic acid
  • benzyloxycarbonyl removed by acidolysis or hydrogenolysis
  • arylalkyl e.g. benzyl, removed by hydrogenolysis
  • arylalkyl e.g. benzyl, removed by hydrogenolysis
  • suitable amine protecting groups include trifluoroacetyl (-COCF 3 ) which may be removed by base catalysed hydrolysis or a solid phase resin bound benzyl group, such as a Merrifield resin bound 2,6-dimethoxybenzyl group (Ellman linker), which may be removed by acid catalysed hydrolysis, for example with trifluoroacetic acid.
  • protected compound of formula (I) is used herein to refer to a compound which includes a protecting group, for example those referred to above.
  • Process (c) may be performed using conventional interconversion procedures such as epimerisation, oxidation, reduction, alkylation, nucleophilic or electrophilic aromatic substitution or amide bond formation.
  • a further process is the preparation of pharmaceutically acceptable salts, and solvates of compounds of formula (I).
  • Compounds of formula (I) and their pharmaceutically acceptable salts may have affinity for and be agonists at the nicotinic ⁇ 7 receptor and are believed to be of potential use in the treatment of neurological diseases including Alzheimer's disease (particularly cognitive deficit of Alzheimer's disease), dementia (including Lewy body dementia and vascular dementia), age-related memory dysfunction, cognitive impairment as listed below, cognitive deficit especially cognitive deficit of schizophrenia, Parkinson's disease and Tourette's syndrome, psychiatric disorders including schizophrenia as listed below, attention deficit/hyperactivity disorder as listed below, depression as listed below, anxiety as listed below and addiction, pain related disorders including pain of neuropathic origin including neuralgias, neuritis and back pain, and inflammatory pain including osteoarthritis, rheumatoid arthritis, acute inflammatory pain and back pain, migraine; and other diseases including obesity, sepsis and gastro-intestinal disorders (including irritable bowel syndrome and inflammatory bowel disease). Further neurological diseases for which these compounds may be of potential use is epilepsy and learning & memory disorders.
  • the following disease classification refer to the classification code in Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, published by the American Psychiatric Association (DSM-IV) and/or the International Classification of Diseases, 10th Edition (ICD- 10):
  • i) Psychotic disorders for example Schizophrenia including the subtypes Paranoid Type (295.30), Disorganised Type (295.10), Catatonic Type (295.20), Undifferentiated Type (295.90) and Residual Type (295.60)); Schizophreniform Disorder (295.40); Schizoaffective Disorder (295.70) (including the subtypes Bipolar Type and Depressive Type); Delusional Disorder (297.1) (including the subtypes Erotomanic Type, Grandiose Type, Jealous Type, Persecutory Type, Somatic Type, Mixed Type and Unspecified Type); Brief Psychotic Disorder (298.8); Shared Psychotic Disorder (297.3); Psychotic Disorder due to a General Medical Condition (including the subtypes with Delusions and with Hallucinations); Substance-Induced Psychotic Disorder (including the subtypes with Delusions (293.81) and with Hallucinations (293.82)); and Psychotic Disorder Not Otherwise Specified (298.9).
  • cognitive impairment including for example the treatment of impairment of cognitive functions including attention, orientation, learning disorders, memory (i.e. memory disorders, amnesia, amnesic disorders, transient global amnesia syndrome and age- associated memory impairment) and language function; cognitive impairment as a result of stroke, Alzheimer's disease, Huntington's disease, Pick disease, Aids-related dementia or other dementia states such as Multiinfarct dementia, alcoholic dementia, hypothyroidism- related dementia, and dementia associated to other degenerative disorders such as cerebellar atrophy and amyotropic lateral sclerosis; other acute or sub-acute conditions that may cause cognitive decline such as delirium or depression (pseudodementia states) trauma, head trauma, age related cognitive decline, stroke, neurodegeneration, drug- induced states, neurotoxic agents, mild cognitive impairment, age related cognitive impairment, autism related cognitive impairment, Down's syndrome, cognitive deficit related to psychosis, and post-electroconvulsive treatment related cognitive disorders; and dyskinetic disorders such as Parkinson's disease, neurodegeneration,
  • Depression and mood disorders for example Depressive Episodes (including Major Depressive Episode, Manic Episode, Mixed Episode and Hypomanic Episode); Depressive Disorders (including Major Depressive Disorder, Dysthymic Disorder (300.4), Depressive Disorder Not Otherwise Specified (311 )); Bipolar Disorders (including Bipolar I Disorder, Bipolar Il Disorder (i.e.
  • Anxiety disorders for example Social Anxiety Disorder; Panic Attack; Agoraphobia, Panic Disorder; Agoraphobia Without History of Panic Disorder (300.22); Specific Phobia (300.29) (including the subtypes Animal Type, Natural Environment Type, Blood-lnjection-lnjury Type, Situational Type and Other Type); Social Phobia (300.23); Obsessive-Compulsive Disorder (300.3); Posttraumatic Stress Disorder (309.81 ); Acute Stress Disorder (308.3); Generalized Anxiety Disorder (300.02); Anxiety Disorder Due to a General Medical Condition (293.84); Substance-Induced Anxiety Disorder; and Anxiety Disorder Not Otherwise Specified (300.00).
  • Specific Phobia (300.29) (including the subtypes Animal Type, Natural Environment Type, Blood-lnjection-lnjury Type, Situational Type and Other Type); Social Phobia (300.23); Obsessive-Compulsive Disorder (300.3); Posttraumatic Stress Disorder (309.81 ); Acute Stress Disorder (308.3); Generalized Anxiety
  • Attention-Deficit /Hyperactivity Disorder including the subtypes Attention-Deficit /Hyperactivity Disorder Combined Type (314.01 ), Attention-Deficit/Hyperactivity Disorder Predominantly Inattentive Type (314.00), Attention-Deficit/Hyperactivity Disorder Hyperactive-Impulse Type (314.01) and Attention-Deficit/Hyperactivity Disorder Not Otherwise Specified (314.9)); Hyperkinetic Disorder; Disruptive Behaviour Disorders such as Conduct Disorder (including the subtypes childhood-onset type (321.81 ), Adolescent- Onset Type (312.82) and Unspecified Onset (312.89), Oppositional Defiant Disorder (313.81 ) and Disruptive Behaviour Disorder Not Otherwise Specified; and Tic Disorders such as Tourette's Disorder (307.23).
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof may be useful in the treatment or prophylaxis of pain. More particularly, a compound of formula (I) or
  • pain includes pain of neuropathic origin including neuralgias, neuritis and back pain; acute pain, chronic pain, chronic articular pain, musculoskeletal pain, inflammatory pain including osteoarthritis, and rheumatoid arthritis, acute inflammatory pain and back pain, visceral pain, pain associated with cancer, pain associated with migraine, tension headache and cluster headaches, pain associated with functional gastrointestinal disorders, lower back and neck pain, pain associated with sprains and strains, sympathetically maintained pain; myositis, pain associated with influenza or other viral infections such as the common cold, pain associated with rheumatic fever, pain associated with myocardial ischemia, post operative pain, headache, toothache and dysmenorrhea.
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof may be useful in the treatment or prophylaxis of chronic pain, post-operative pain, chronic lower back and neck pain, cancer pain, sprains and strains. More particularly, a compound of formula (I) or a pharmaceutically acceptable salt thereof may be useful in a treatment of these pain conditions.
  • treatment refers to symptomatic treatment.
  • Chronic articular pain conditions include rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gouty arthritis and juvenile arthritis.
  • Pain associated with functional gastrointestinal disorders includes non-ulcer dyspepsia, non-cardiac chest pain and irritable bowel syndrome.
  • the invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use in therapy for example in the treatment or prophylaxis of the above disorders, in particular pain, neurological (e.g. cognitive deficit of Alzheimer's disease) and psychiatric disorders (e.g. cognitive deficit of schizophrenia). More particularly, a compound of formula (I) or a pharmaceutically acceptable salt thereof may be useful in the treatment or pain.
  • the invention further provides a method of treatment of the above disorders, in mammals including humans, which comprises administering to the sufferer a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment or prophylaxis of the above disorders.
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof is usually formulated in a standard pharmaceutical composition.
  • Such compositions can be prepared using standard procedures.
  • the present invention further provides a pharmaceutical composition for use in the treatment or prophylaxis of the above disorders which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • the present invention further provides a pharmaceutical composition which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof may be used in combination with other medicaments indicated to be useful as either disease modifying or symptomatic treatments of Alzheimer's disease.
  • Suitable examples of such other therapeutic agents may be agents known to modify cholinergic transmission such as 5-HT 1A antagonists, (e.g. lecozotan), 5-HT6 antagonists, M1 muscarinic agonists, M2 muscarinic antagonist, acetylcholinesterase inhibitors (e.g tetrahydroaminoacridine, donepezil or rivastigmine), or allosteric modulators, nicotinic receptor agonists or allosteric modulators, symptomatic agents such as 5-HT6 receptor antagonists, e.g. SB742457, H3 receptor antagonists e.g.
  • 5-HT 1A antagonists e.g. lecozotan
  • 5-HT6 antagonists e.g. lecozotan
  • M1 muscarinic agonists e.g. M2 muscarinic antagonist
  • acetylcholinesterase inhibitors e.g tetrahydroaminoacrid
  • GSK189254 and GSK239512 5-HT4 receptor agonist, PPAR agonists, also NMDA receptor antagonists or modulators, also disease modifying agents such as ⁇ or v- secretase inhibitors (e.g. R-flurbiprofen), also AMPA positive modulators and Glycine Transporter Reuptake inhibitors.
  • the compound of formula (I) or a pharmaceutically acceptable salt thereof may be used in combination with other medicaments indicated to be useful in the treatment of pain of neuropathic origin including neuralgias, neuritis and back pain, and inflammatory pain including osteoarthritis, rheumatoid arthritis, acute inflammatory pain, back pain and migraine.
  • Such therapeutic agents include for example COX-2 (cyclooxygenase-2 ) inhibitors, such as celecoxib, deracoxib, rofecoxib, valdecoxib, parecoxib, COX-189 or 2-(4-ethoxy-phenyl)-3-(4-methanesulfonyl-phenyl)-pyrazolo[1 ,5- b]pyridazine (WO99/012930); 5-lipoxygenase inhibitors; NSAIDs (non-steroidal antiinflammatory drugs) such as diclofenac, indomethacin, nabumetone or ibuprofen; bisphosphonates, leukotriene receptor antagonists; DMARDs (disease modifying antirheumatic drugs) such as methotrexate; adenosine A1 receptor agonists; sodium channel blockers, such as lamotrigine; NMDA (N-methyl-D-aspartate) receptor modulators
  • COX-2 inhibitors are disclosed in US Patent Nos. 5,474,995, US5,633,272; US5,466,823, US6,310,099 and US6.291.523; and in WO 96/25405, WO 97/38986, WO 98/03484, WO 97/14691 , WO99/12930, WO00/26216, WO00/52008, WO00/38311 , WO01/58881 and WO02/18374.
  • the compounds may be administered either sequentially or simultaneously by any convenient route.
  • the invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof together with a further therapeutic agent or agents.
  • the combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations comprising a combination as defined above together with a pharmaceutically acceptable carrier or excipient comprise a further aspect.
  • the individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations.
  • each compound may differ from that when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art.
  • a pharmaceutical composition which may be prepared by admixture, suitably at ambient temperature and atmospheric pressure, is usually adapted for oral, parenteral or rectal administration and, as such, may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable or infusible solutions or suspensions or suppositories. Orally administrable compositions are generally preferred.
  • Tablets and capsules for oral administration may be in unit dose form, and may contain conventional excipients, such as binding agents, fillers, tabletting lubricants, disintegrants and acceptable wetting agents.
  • the tablets may be coated according to methods well known in normal pharmaceutical practice.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspension, solutions, emulsions, syrups or elixirs, or may be in the form of a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, and, if desired, conventional flavourings or colorants.
  • fluid unit dosage forms may be prepared utilising a compound of the invention or pharmaceutically acceptable salt or solvate thereof and a sterile vehicle.
  • the compound depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle.
  • the compound can be dissolved for injection and filter sterilised before filling into a suitable vial or ampoule and sealing.
  • adjuvants such as a local anaesthetic, preservatives and buffering agents are dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum.
  • Parenteral suspensions are prepared in a similar manner, except that the compound is suspended in the vehicle instead of being dissolved, and sterilisation cannot be accomplished by filtration.
  • the compound can be sterilised by exposure to ethylene oxide before suspension in a sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
  • the composition may contain from 0.1% to 99% by weight, preferably from 10% to 60% by weight, of the active material, depending on the method of administration.
  • the dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof used in the treatment of the aforementioned disorders will vary in the usual way with the seriousness of the disorders, the weight of the sufferer, and other similar factors.
  • suitable unit doses may be 0.05 to 1000 mg, more suitably 1.0 to 200 mg, and such unit doses may be administered more than once a day, for example two or three a day. Such therapy may extend for a number of weeks, months, years or even life.
  • a further aspect to the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising 0.05 to IOOOmg of a compound of formula (I) or a pharmaceutically acceptable salt thereof, and 0 to 3 g more suitably 0 to 2g of at least one pharmaceutically acceptable carrier.
  • EDAC.HCI/EDAC 1-Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride
  • Biotage SP4 Four column sequential FLASH purification system with expanded fraction bed designed for multiple sample purification, Website: http://www.biotage.com/ SCX Strong Cationic Exchange Resin used for isolation of amines, Website: http://www.biotage.com/
  • reaction mixture was cooled to room temperature before the white precipitate was filtered and the filtrate passed through an SCX column (eluting with 100% methanol followed by 10% 2M ammonia in methanol) to afford 4-(4-morpholinyl)butyl]amine (1.8g, 41%).
  • Examples 2-7 were prepared in an analogous manner to Example 1. Where mentioned, hydrochloride salts were prepared.
  • Methyl-5-indole carboxylate (1g, 5.7mmol) was added to a round bottom flask and dissolved in DMF (10ml) and cooled to 0 0 C with an ice bath. N-Bromosuccinimide (1.07g, 5.99mmol) dissolved in DMF (20ml) was added slowly. The reaction mixture was stirred at 0 0 C for 30min then at room temperature overnight. After stirring for 17.5h, LC-MS showed no starting material and one peak corresponding to methyl 3-bromo-1 H-indole-5- carboxylate. The solvent was removed under vacuum to give a brown solid. To this was added 40ml water and 50ml ethyl acetate.
  • Methyl 3-phenyl 1-H indole-5-carboxylate (0.65g, 2.59mmol) was added to a round bottom flask and dissolved in methanol (20ml). To this was added hydrazine hydrate (1.5ml, 25.9mmol) and the reaction mixture heated at 80 0 C for 42h. The reaction was further heated at 90 0 C for 63h after adding additional hydrazine hydrate (1.2ml, 48.4mmol). The reaction was passed through a 7Og SCX column using methanol followed by 2M ammonia in methanol. The fractions eluted with 2M ammonia in methanol were collected. TLC showed most fractions were not pure.
  • the collected fractions were concentrated and purified by SP4 silica column (Solvent systems: DCM and 10% 2M ammonia in methanol/DCM).
  • the target product was eluted at 5% 2M ammonia in methanol/DCM gradient.
  • the purified fractions were collected and dried down to afford product.
  • the product (230mg) was then dissolved in 2 ml methanol and 10ml 1 M HCI. The solution was heated at 60 0 C for 3h. The solvents were removed in vacuo to afford 3-phenyl-1 H-indole-5- carbohydrazide as a light beige solid (220mg).
  • Example 13-17 were prepared in an analogous manner to Example 12. Where indicated, hydrochloride salts of the compounds were prepared.
  • Methyl 1 H-indole-3-carboxylate (1g, 5.7mmol), K 3 PO 4 (2.54g, 11.97mmol), copper iodide (54.27mg, 0.29mmol), trans N-N-dimethyl-i ⁇ -cyclohexanediamine (6.38mg, O.O ⁇ mmol) and iodobenzene (1.4g, 6.8mmol) were added to a 25ml round bottom flask with toluene (12ml) as a solvent. The reaction mixture was stirred at 110 0 C under argon overnight. The reaction lasted 2 days.
  • Example 18 5-(1 -Phenyl-1 H-indol-3-yl)-N-[3-(1 -piperidinyl)propyl]-1 ,3,4-oxadiazol-2- amine
  • Example 20 was prepared in a similar manner to Example 19, however in the preparation of the methyl 2-phenyl-1 ,3-benzoxazole-6-carboxylate intermediate, a different catalyst Pb(OAc) 2 , conditions and solvents were used.
  • Example 21 was prepared in a similar manner however the methyl 3-amino-4-(phenylamino)benzoate was prepared from the corresponding nitro compound by reduction, which in turn was prepared from methyl 4- bromo-3-nitrobenzoate and phenylamine.
  • Examples 24-25 were prepared in an analogous manner to Example 23. Where indicated, the hydrochloride salt was prepared.
  • Examples 28-32 were prepared in an analogous manner to Example 26. In the preparation of the compound of Example 32, the appropriate acid was used to make the hydrazide rather than via the Boc protected intermediate.
  • Example 33 ⁇ /-[4-(4-Morpholinyl)butyl]-5-(1H-pyrrolo[2,3-fe]pyridin-4-yl)-1,3,4- oxadiazol-2 -amine
  • Example 35 ⁇ /-[4-(4-Morpholinyl)butyl]-5-(1H-pyrrolo[2,3-fe]pyridin-2-yl)-1,3,4- oxadiazol-2 -amine
  • Example 36 ⁇ /-[4-(4-Morpholinyl)butyl]-5-(1 H-pyrrolo[2,3-fe]pyridin-3-yl)-1 ,3,4- oxadiazol-2 -amine
  • the reaction mixture was heated at 8O 0 C for 2.5h.
  • nAChRs are non-selective cation channels with high permeability to Ca 2+ . These studies were carried out by measuring changes of intracellular Ca 2+ concentration using the
  • GH4C1 cells pituitary tumor, immortalized cell line
  • human ⁇ 7 nAChR Biocat ID 96986
  • growth medium Ham's Nutrient Mixture F10 - Ham's F10, Invitrogen 31550-023, 15% Horse Serum heat inactivated - Invitrogen 26050-047, 2.5% Foetal Bovine Serum - FBS, Gibco 10500-064, 200 ⁇ g/ml Hygromycin B - Invitrogen, 10687-010, 10 mg/L Phenol Red - Sigma, P 0290, 1 mM Glutamine - Invitrogen, 25030-024) and plated in 500 cm 2 Triple Flask.
  • cells growing in suspension were harvested, centrifuged, resuspended in growth medium at a density of 1.8 x 10 5 /mL and plated in coated clear bottom black 384 wells plates (Pierce) at 9000 cells/well. Cells were then incubated at 30 0 C, 5% CO 2 for 72 hours.
  • the dye was then diluted with AB to a final concentration of 2 ⁇ M and placed on the cells. After 45- 60 minutes dye loading incubation at 37°C, the unincorporated dye was removed from the cells by washing (80 ⁇ L, 3 times) with AB, and a final volume of 30 ⁇ L/well of AB was left in each well. Plates containing test compounds (dissolved in 100% DMSO at 2 mM and serially diluted with DMSO) were copied into "daughter" plates (1 ⁇ L/well dispensation). Just prior to starting the assay, the "daughter" plate was diluted with 50 ⁇ L/well of AB.
  • Examples 1 , 26 and 28 were tested in the ⁇ 7 nAChR FLI PR® assay and had a pEC50 of > than 7.
  • a pEC50 is the negative logarithm of the agonist EC50 calculation as determined in the ⁇ 7 nAChR FLIPR® assay. Certain Examples have been tested more than once. Variations in pEC50 may arise between tests.
  • nAChRs are non-selective cation channels with high permeability to Ca 2+ . These studies were carried out by measuring changes of intracellular Ca 2+ concentration using the
  • GH4C1 cells pituitary tumor, immortalized cell line
  • human ⁇ 7 nAChR Biocat ID 96986
  • growth medium Ham's Nutrient Mixture F10 - Ham's F10, Invitrogen 11550-043, 15% Horse Serum heat inactivated - Invitrogen 26050-088, 2.5% Foetal Bovine Serum heat inactivated - FBS, Gibco 10500- 064, 200 ⁇ g/ml Hygromycin B - Invitrogen, 10687-010, 10 mg/L Phenol Red - Sigma, P 0290, 1 mM Glutamine - Invitrogen, 25030-024) and seeded in 175 cm 2 Flasks.
  • cells growing in semi-suspension were harvested, centrifuged, resuspended in growth medium at a density of 8 x 10 5 /ml_ and plated in poly-D- lysine coated clear bottom, black wall, 96 well plates (BD Bioscience) at 80,000 cells/well. Cells were then incubated at 30 0 C, 5% CO 2 for 72 hours.
  • the dye was then diluted with AB to a final concentration of 2 ⁇ M and placed on the cells. After 45 minutes dye loading incubation at 37°C, the unincorporated dye was removed from the cells by washing (200 ⁇ L, 3 times) with AB, and a final volume of 150 ⁇ L/well of AB was left in each well.
  • Examples 1 , 2, 8 and 22 exhibited a pEC50 value ⁇ 7.
  • the compound of Example 11 did not appear to have activity in this assay.

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Abstract

L'invention porte sur des dérivés d'oxadiazole représentés par la formule (I) où le noyau A est un système bicyclique ou tricyclique. Les composés revendiqués sont actifs sur les récepteurs nicotiniques de l'acétylcholine (nAChR) et sont utiles pour traiter des troubles neurologiques, psychiatriques et gastro-intestinaux, ainsi que la septicémie et l'obésité.
PCT/EP2008/066699 2007-12-05 2008-12-03 Dérivés d'oxadiazole et leur utilisation comme modulateurs des récepteurs nicotiniques de l'acétylcholine WO2009071577A1 (fr)

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