WO2001016107A1 - Arylalkyloxyalkylamines et arylalkylthioalkylamines, compositions pharmaceutiques les contenant et leur utilisation en tant qu'inhibiteurs des recepteurs cholinergiques nicotiniques - Google Patents

Arylalkyloxyalkylamines et arylalkylthioalkylamines, compositions pharmaceutiques les contenant et leur utilisation en tant qu'inhibiteurs des recepteurs cholinergiques nicotiniques Download PDF

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WO2001016107A1
WO2001016107A1 PCT/US2000/017978 US0017978W WO0116107A1 WO 2001016107 A1 WO2001016107 A1 WO 2001016107A1 US 0017978 W US0017978 W US 0017978W WO 0116107 A1 WO0116107 A1 WO 0116107A1
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compound
methyl
nitrogen
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pyridyl
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Gary Maurice Dull
Jared Miller Wagner
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Targacept, Inc.
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Priority to EP00945006A priority Critical patent/EP1212301A1/fr
Priority to CA002383307A priority patent/CA2383307A1/fr
Priority to AU59007/00A priority patent/AU5900700A/en
Publication of WO2001016107A1 publication Critical patent/WO2001016107A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/30—Oxygen atoms
    • 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
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
    • C07D213/32—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/61—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/65—One oxygen atom attached in position 3 or 5
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • 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

Definitions

  • the present invention relates to pharmaceutical compositions, and particularly pharmaceutical compositions incorporating compounds that are capable of affecting nicotinic cholinergic receptors. More particularly, the present invention relates to compounds capable of activating nicotinic cholinergic receptors, for example, as agonists of specific nicotinic receptor subtypes. The present invention also relates to methods for treating a wide variety of conditions and disorders, and particularly conditions and disorders associated with dysfunction of the central and autonomic nervous systems.
  • Nicotine has been proposed to have a number of pharmacological effects. See, for example, Pullan et al. N. Engl. J. Med. 330:811-815 (1994). Certain of those effects may be related to effects upon neurotransmitter release. See for example, Sjak-shie et al., Brain Res. 624:295 (1993), where neuroprotective effects of nicotine -ire proposed. Release of acetylcholine and dopamine by neurons upon administration of nicotine has been reported by Rowell et al., J. Neurochem. 43:1593 (1984); Rapier et a J. Neurochem. 50:1123 (1988); Sandor et al., Br in Res. 567:313 (1991) and Vizi, Br.
  • CNS Central Nervous System
  • CNS disorders are a type of neurological disorder.
  • CNS disorders can be drug induced; can be attributed to genetic predisposition, infection or trauma; or can be of unknown etiology.
  • CNS disorders comprise neuropsychiatric disorders, neurological diseases and mental illnesses; and include neurodegenerative diseases, behavioral disorders, cognitive disorders and cognitive affective disorders.
  • CNS disorders There are several CNS disorders whose clinical manifestations have been attributed to CNS dysfunction (i.e., disorders resulting from inappropriate levels of neurotransmitter release, inappropriate properties of neurotransmitter receptors, and/or inappropriate interaction between neurotransmitters and neurotransmitter receptors).
  • CNS disorders can be attributed to a cholinergic deficiency, a dopaminergic deficiency, an adrenergic deficiency and/or a serotonergic deficiency.
  • CNS disorders of relatively common occurrence include presenile dementia (early onset Alzheimer's disease), senile dementia (dementia of the Alzheimer's type), Parkinsonism including Parkinson's disease, Huntington's chorea, tardive dyskinesia, hyperkinesia, mania, attention deficit disorder, anxiety, dyslexia, schizophrenia and Tourette's syndrome.
  • CNS diseases e.g., CNS diseases
  • a pharmaceutical composition incorporating a compound which interacts with nicotinic receptors, such as those which have the potential to effect the functioning of the CNS, but which compound when employed in an amount sufficient to effect the functioning of the CNS, does not significantly effect those receptor subtypes which have the potential to induce undesirable side effects (e.g., appreciable activity at skeletal muscle sites).
  • the present invention relates to arylalkyloxyalkylamine and arylalkylthioalkylamine compounds.
  • arylmethoxyalkylamines and arylmethylthioalkylamines are arylmethoxyalkylamines and arylmethylthioalkylamines, such as pyridylmethoxyalkylamines and pyridylmethylthioalkylamines.
  • the present invention also relates to prodrug derivatives of the compounds of the present invention.
  • Exemplary compounds of the present invention include methyl(3-(3- pyridylmethoxy)propyl)amine, 3-pyridyl(pyrrolidin-2-ylmethoxy)methane, methyl(l - methyl-2-(3-pyridylmethoxy)ethyl)amine, (3-((3-pyridyl)methoxy) propyl) dimethylamine, (2-((5-bromo-3-pyridyl)methoxy)ethyl)methylamine, methyl(2-((5- methoxy-3-pyridyl)methoxy)ethyl)amine, (2-((3-quinolyl)methoxy)ethyl) methylamine, methyl(2-(pyrimidin-5-ylmethoxy)ethyl)amine, 3-((3-pyridyl) methoxy)quinuclidine, (3 -pyridyl)quinuclidin-2-ylme
  • the present invention also relates to methods for the prevention or treatment of a wide variety of conditions or disorders, and particularly those disorders characterized by disfunction of nicotinic cholinergic neurotransmission including disorders involving neuromodulation of neurotransmitter release, such as dopamine release.
  • the present invention also relates to methods for the prevention or treatment of disorders, such as central nervous system (CNS) disorders, which are characterized by an alteration in normal neurotransmitter release.
  • CNS central nervous system
  • the present invention also relates to methods for the treatment of certain conditions (e.g., a method for alleviating pain). The methods involve administering to a subject an effective amount of a compound of the present invention.
  • the present invention in another aspect, relates to a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of a compound of the present invention.
  • a pharmaceutical composition incorporates a compound which, when employed in effective amounts, has the capability of interacting with relevant nicotinic receptor sites of a subject, and hence has the capability of acting as a therapeutic agent in the prevention or treatment of a wide variety of conditions and disorders, particularly those disorders characterized by an alteration in normal neurotransmitter release.
  • Preferred pharmaceutical compositions comprise compounds of the present invention.
  • compositions of the present invention are useful for the prevention and treatment of disorders, such as CNS disorders, which are characterized by an alteration in normal neurotransmitter release.
  • the pharmaceutical compositions provide therapeutic benefit to individuals suffering from such disorders and exhibiting clinical manifestations of such disorders in that the compounds within those compositions, when employed in effective amounts, have the potential to (i) exhibit nicotinic pharmacology and affect relevant nicotinic receptors sites (e.g., act as a pharmacological agonist to activate nicotinic receptors), and (ii) elicit neurotransmitter secretion, and hence prevent and suppress the symptoms associated with those diseases.
  • the compounds are expected to have the potential to (i) increase the number of nicotinic cholinergic receptors of the brain of the patient, (ii) exhibit neuroprotective effects and (iii) when employed in effective amounts do not cause appreciable adverse side effects (e.g., significant increases in blood pressure and heart rate, significant negative effects upon the gastro-intestinal tract, and significant effects upon skeletal muscle).
  • the pharmaceutical compositions of the present invention are believed to be safe and effective with regards to prevention and treatment of a wide variety of conditions and disorders.
  • the compounds of the present invention include compounds of the formula:
  • each of X, X', X", Y' and Y" are individually nitrogen, nitrogen bonded to oxygen (e.g., an N-oxide or N-O functionality) or carbon bonded to a substituent species characterized as having a sigma m value greater than 0, often greater than 0.1, and generally greater than 0.2, and even greater than 0.3; less than 0 and generally less than -0.1; or 0; as determined in accordance with Hansch et al., Chem. Rev. 91:165 (1991).
  • substituent species When any of X, X', X", Y' and Y" are carbon bonded to a substituent species, those substituent species typically have a sigma m value between about -0.3 and about 0.75, frequently between about -0.25 and about 0.6; and each sigma m value individually can be 0 or not equal to zero.
  • sigma m value between about -0.3 and about 0.75, frequently between about -0.25 and about 0.6; and each sigma m value individually can be 0 or not equal to zero.
  • X is CH, CBr or COR', where R' preferably is benzyl, methyl, ethyl, isopropyl, isobutyl, tertiary butyl or cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl). Most preferably, X" is nitrogen.
  • X is C-NR'R", C- OR' or C-NO 2 , typically C-NH 2 , C-NHCH 3 or C-N(CH 3 ) 2 , with C-NH 2 being preferred.
  • both X' and X" are nitrogen.
  • X, Y' and Y" each are carbon bonded to a substituent species, and it is typical that X, Y' and Y" each are carbon bonded to a substituent species such as hydrogen.
  • X, Y' and Y" usually include hydrogen, halo (e.g., F, Cl, Br, or I), alkyl (e.g., lower straight chain or branched C ⁇ -8 alkyl, but preferably methyl or ethyl), or NR'R", where in such case R' and R" are individually hydrogen or lower alkyl, including CrC 8 , preferably C 1 -C 5 alkyl.
  • X is CH and Y' is CH.
  • X and Y' both are CH, and Y" is carbon bonded to a non-hydrogen substituent species, such as -NR'R", -OR' or -NO 2 , with -NHCH 3 or -N(CH 3 ) being preferred and with -NH 2 being most preferred.
  • a non-hydrogen substituent species such as -NR'R", -OR' or -NO 2 , with -NHCH 3 or -N(CH 3 ) being preferred and with -NH 2 being most preferred.
  • Adjacent substituents of X, X', Y", X" and Y' can combine to form one or more saturated or unsaturated, substituted or unsubstituted carbocyclic or heterocyclic rings containing, but not limited to, ether, acetal, ketal, amine, ketone, lactone, lactam, carbamate, or urea functionalities.
  • m is an integer and n is an integer such that the sum of m plus n is 2, 3, 4 or 5, preferably is 2 or 3, and more preferably is 3.
  • the substituents of either X, X', X", Y' and Y" can include hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, heterocyclyl (e.g., beta-styryl), substituted heterocyclyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, acyl, alkoxycarbonyl and aryloxycarbonyl functionalities.
  • heterocyclyl e.g., beta-styryl
  • the substituents of X, X', X", Y' and Y" individually usually include hydrogen, halo (e.g., F, Cl, Br, or I), alkyl (e.g., lower straight chain or branched C 1-8 alkyl, but preferably methyl or ethyl), or NR'R", where in such case R' and R" are individually hydrogen or lower alkyl, including - , preferably -C 5 alkyl.
  • halo e.g., F, Cl, Br, or I
  • alkyl e.g., lower straight chain or branched C 1-8 alkyl, but preferably methyl or ethyl
  • NR'R where in such case R' and R" are individually hydrogen or lower alkyl, including - , preferably -C 5 alkyl.
  • R' and R" can be straight chain or branched alkyl, or R' and R" can form a cycloalkyl funtionality (e.g., cyclopropyl cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, and quinuclidinyl).
  • Representative aromatic group-containing species include pyridinyl, quinolinyl, pyrimidinyl, phenyl, and benzyl (where any of the foregoing can be suitably substituted with at least one substituent group, such as alkyl, halo, or amino substituents).
  • Other representative aromatic ring systems are set forth in Gibson et al., J. Med. Chem. 39:4065 (1996).
  • E, E 1 , E ⁇ and E ⁇ individually represent hydrogen or a suitable non-hydrogen substituent (e.g., alkyl, substituted alkyl, halo substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclyl, substituted heterocyclyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl or substituted arylalkyl), preferably lower alkyl (e.g., straight chain or branched alkyl including C ⁇ -C 8 , preferably -C 5 , such as methyl, ethyl, or isopropyl) or halo substituted lower alkyl (e.g., straight chain or branched alkyl including C]-C 8 , preferably C 1 -C 5 , such as trifluoromethyl or trichloromethyl).
  • a suitable non-hydrogen substituent e.g., alkyl, substituted al
  • E, E 1 , E ⁇ and E ⁇ are hydrogen, or at least one of E, E 1 , E 11 and E ⁇ is non-hydrogen and the remaining E, E 1 , E ⁇ and E m are hydrogen.
  • E and E 1 each can be hydrogen; or when m is 2 and n is 1, E, E 1 , E ⁇ and E m all can be hydrogen, or E, E 1 and E ⁇ can be hydrogen and E ⁇ can be methyl; or when m is 1 and n is 2, E 1 , E 11 and E ⁇ l can be hydrogen and E can be methyl.
  • the selection of m, n, E, E 1 , E ⁇ and E ⁇ is such that 0, 1 or 2, usually 0 or 1, of the substituents designated as E, E 1 , E ⁇ and E ⁇ are non-hydrogen (e.g., substituents such as alkyl or halo-substituted alkyl).
  • substituents such as alkyl or halo-substituted alkyl.
  • compounds of the present invention have chiral centers, and the present invention relates to racemic mixtures of such compounds as well as enamiomeric compounds.
  • B is represented by the bridging species -(CE IV E V ) j -B 1 -, where E IV and E v individually represent those species previous described for E, E 1 , E ⁇ and E m ; j is 1 or 2, most preferably 1 ; B is oxygen or sulfur, most preferably oxygen.
  • E IV and E v most preferably are hydrogen or lower alkyl, with at least one of E IV and E v being hydrogen, and most preferably all of E IV and E v are hydrogen.
  • B 1 can be -CH 2 -O-.
  • Q is represented by N Z' Z"; where Z' and Z" individually represent hydrogen or lower alkyl (e.g., straight chain or branched alkyl including C ⁇ -C & , preferably d- C 5 , such as methyl, ethyl, or isopropyl), substituted alkyl, acyl, alkoxycarbonyl, or aryloxycarbonyl; and preferably Z' is hydrogen or methyl, and Z" is hydrogen.
  • Z' and Z" individually represent hydrogen or lower alkyl (e.g., straight chain or branched alkyl including C ⁇ -C & , preferably d- C 5 , such as methyl, ethyl, or isopropyl), substituted alkyl, acyl, alkoxycarbonyl, or aryloxycarbonyl; and preferably Z' is hydrogen or methyl, and Z" is hydrogen.
  • the associated carbon and nitrogen atoms can combine to form a monocyclic ring structure such as azetidinyl, pyrrolidinyl, piperidinyl or piperazinyl (optionally substituted with pyridinyl, such as 3-pyridinyl, or pyrimidinyl, such 5-pyridinyl) or a bicyclic ring structure such as 3-(2-azabicyclo[4.2.0]octyl), 3- (2-azabicyclo[2.2.2]octyl), or 3-(2-azabicyclo[2.2.1]heptyl).
  • a monocyclic ring structure such as azetidinyl, pyrrolidinyl, piperidinyl or piperazinyl (optionally substituted with pyridinyl, such as 3-pyridinyl, or pyrimidinyl, such 5-pyridinyl) or a bicyclic ring structure such as 3-(2-azabicyclo[4.2.0]octy
  • alkyl refers to straight chain or branched alkyl radicals including CrC 8 , preferably C ⁇ -C 5 , such as methyl, ethyl, or isopropyl; "substituted alkyl” refers to alkyl radicals further bearing one or more substituent groups such as hydroxy, alkoxy, mercapto, aryl, heterocyclo, halo, amino, carboxyl, carbamyl, cyano, and the like; "alkenyl” refers to straight chain or branched hydrocarbon radicals including d-Q, preferably Cj-C 5 and having at least one carbon-carbon double bond; “substituted alkenyl” refers to alkenyl radicals further bearing one or more substituent groups as defined above; "cycloalkyl” refers to saturated or unsaturated cyclic ring- containing radicals containing three to eight carbon atoms, preferably three to six carbon atoms; "substituted
  • Z" is hydrogen, and Z' is hydrogen or methyl; preferably m is 1, 2 or 3, and n is 1; preferably each of E and E' is hydrogen, and preferably E' is hydrogen or methyl, but most preferably all of E and E' are hydrogen; preferably, each of E" and E'" is hydrogen, and preferably E'" is hydrogen or methyl; preferably Y" is carbon bonded to a substituent species, and most preferably, that substituent species is hydrogen, halo, NR'R" or OR"; preferably X" is nitrogen or carbon bonded to a substituent species such as NR'R", NO or OR", but most preferably is nitrogen; preferably X' is nitrogen, but also preferably is carbon bonded to a substituent species such as hydrogen, R', halo, OR', NR'R", CN, C 2 R' or CHCHR'; preferably both R' and R" are hydrogen, but either or both of R'
  • Representative compounds of the present invention include the following: methyl(3-(phenylmethoxy)propyl)amine, methyl(3-((3-methoxyphenyl)methoxy)propyl)amine, methyl(3-((4-methoxyphenyl)methoxy)propyl)amine,
  • Certain arylmethoxyalkylamine compounds of the present invention can be prepared by the alkylation of certain phenylcarbinols (benzyl alcohols) with a 1,3-dihalopropane, such as 1,3-dichloropropane, 1,3- dibromopropane, 1,3-diiodopropane, or l-chloro-3-iodopropane, which are commercially available from Aldrich Chemical Company, in the presence of a base (e.g., sodium hydride) in dry N,N-dimethylformamide.
  • a base e.g., sodium hydride
  • the resulting 3-halo-l- phenylmethoxypropane can be converted to a phenylmethoxyalkylamine, such as methyl(3-(phenylmethoxy)propyl)amine, by treatment with methylamine in a solvent, such as tetrahydrofuran or aqueous methanol.
  • a solvent such as tetrahydrofuran or aqueous methanol.
  • Certain pyridylmethoxyalkylamine compounds can be prepared by the alkylation of 3-pyridylcarbinol with a 1,3-dihalopropane such as 1,3-dichloropropane, 1,3-dibromopropane, 1,3-diiodopropane, or l-chloro-3-iodopropane (commercially available from Aldrich Chemical Company) in the presence of a base, such as sodium hydride, in dry N,N-dimethylformamide.
  • a base such as sodium hydride
  • the resulting 3-halo-l- pyridylmethoxypropane such as 3-chloro-l-(3-pyridylmethoxy)propane
  • a pyridylmethoxyalkylamine such as methyl(3-(3- pyridylmethoxy)propyl)amine by treatment with an excess of aqueous methylamine in a solvent such as tetrahydrofuran or methanol assisted by heating.
  • methyl (2-(3- pyridylmethoxy)ethylamine can be provided in a similar manner.
  • 3- pyridylcarbinol can be alkylated with the p-toluenesulfonate ester of N-(tert- butoxycarbonyl)butoxycarbonyl-N-methylethanolamine using sodium hydride in N,N-dimethyformamide.
  • the protecting group of the resulting N-butoxycarbonyl pyridylmethoxyethanolamine compound can be removed by treatment with a strong acid such as trifluoroacetic acid to produce methyl(2-(3-pyridylmethoxy)ethylamine.
  • Certain pyridylmethoxyalkylamines that possess a branched side chain, such as methyl(l -methyl-3 -(3 -pyridy lmethoxy)propyl)amine can be prepared by alkylating 3-pyridylcarbinol with a 1,3-dihalobutane, such as 1,3-dibromobutane, in the presence of a base such as sodium hydride in dry N,N-dimethylformamide.
  • Chiral starting materials are available for the synthesis of the pure enantiomers of the branched chain pyridylmethoxyalkylamines, such as (1R)- and (lS)-methyl(l- methyl-3-(3-pyridylmethoxy)propyl)amine.
  • One approach can be carried out using either methyl (R)-(-)-3-hydroxybutyrate or the (+)-enantiomer, (S)-(+)-3- hydroxybutyrate, both of which are available from Aldrich Chemical Company.
  • (R)-(-)-3-hydroxybutyrate can be converted to (R)-(-)-3- tetrahydropyranyloxybutyl bromide, using the procedures set forth in Yuasa et al., J. Chem. Soc, Perk. Trans. 1(5): 465 (1996).
  • Alkylation of 3-pyridylcarbinol with (R)- (-)-3-tetrahydropyranyloxybutyl bromide using sodium hydride in N,N- dimethylformamide produces the tetrahydropyranyl ether of 4-(3 -pyridy loxy)butan- (2R)-ol.
  • (S)-(+)-3-hydroxybutyrate can be converted to (S)-(+)-3-tetrahydropyranyloxybutyl bromide using the procedures set forth in Sakai et a ⁇ ., Agric. Biol. Chem. 50(6): 1621 (1986).
  • This protected bromo alcohol can be converted to the corresponding chiral pyridylmethoxyalkylamine, (lR)-methyl(l-methyl-3-(3-pyridylmethoxy)propyl)amine, using a sequence involving alkylation of 3-pyridylcarbinol, removal of the tetrahydropyranyl group, tosylation, and methylamine displacement of the intermediate tosylate.
  • the resulting butoxycarbonyl-protected amine can be deprotected using trifluoroacetic acid or hydrochloric acid to produce (1R)- and (1S)- methyl(l-methyl-2-(3-pyridylmethoxy)ethyl)amine.
  • the requisite tosylate esters of the chiral aminopropanols can be prepared from either N-methyl-L-alanine or N- methyl-D-alanine (both available from Sigma Chemical Company) using methodology similar to that reported by Schlessinger et al., Tetrahedron Lett. 28:2083-2086 (1987).
  • N-methyl-L-alanine or N-methyl-D-alanine can be reacted sequentially with lithium aluminum hydride (to give the corresponding N- methyl aminopropanols) di-tert-butyl dicarbonate (to protect the amino group), and p- toluenesulfonyl chloride (to esterify the alcohol).
  • Certain pyridylmethoxyalklylamines that possess a branched side chain can be prepared by alkylating 3-pyridylcarbinol with a protected 3 -hydroxy- 1 -halobutane, such as 3-[(tert- butyl)dimethylsilyloxy]-l-bromobutane (prepared according to the procedures set forth in Gerlach et al., Helv. Chim. Ada.
  • pyridylmethoxyalkylamines possessing a branched side chain such as (l-methyl-3-(3-pyridyloxy)propyl)methylamine
  • pyridylmethoxyalkylamines possessing a branched side chain can be synthesized by alkylating 3-pyridylcarbinol with a protected l-iodo-3-butanone, namely 2-methyl-2- (2-iodoethyl)-l,3-dioxolane, with is prepared according to the procedures set forth in Stowell et al., J. Org. Chem. 48: 5381 (1983).
  • the resulting ketal can be deprotected by treatment with aqueous acetic acid or p-toluenesulfonic acid in methanol to yield 4-(3-pyridylmethoxy)butan-2-one.
  • Reductive amination of the resulting ketone using methylamine and sodium cyanoborohydride according to the methodology set forth in Borch, Org. Syn. 52: 124 (1972) provides (l-methyl-3-(3-pyridylmethoxy)propyl) methylamine.
  • the intermediate, 4-(3-pyridylmethoxy)butan-2-one can be reduced with sodium borohydride to yield an alcohol, 4-(3 -pyridy lmethoxy)butan- 2-ol.
  • Mesylation or tosylation of that alcohol, followed by mesylation or tosylation displacement using methylamine provides the branched chain pyridylmethoxyalkylamine, methyl(l-methyl-3-(3-pyridyloxy)propyl)amine.
  • 5-substituted-3-pyridylmethoxyalkylamine compounds of the present invention can be synthetically produced.
  • 5 -bromo-3 -pyridy lmethoxy-containing compounds can be prepared using a combination of synthetic techniques known to those skilled in the art.
  • 5-bromo- substituted analogs of methyl(3-(3-pyridylmethoxy)propyl)amine, methyl(2-(3- pyridylmethoxy)ethyl)amine, methyl(l-methyl-3-(3-pyridylmethoxy)propyl)amine, methyl(l-methyl-2-(3 -pyridy lmethoxy)ethyl)amine and other compounds of the present invention can all be prepared starting from 5 -bromo-3 - hydroxymethylpyridme, which in turn can be prepared from 5-bromonicotinic acid (available from Aldrich Chemical Company).
  • 5-bromonicotinic acid is converted to the mixed anhydride with ethyl chloroformate and reduced with lithium aluminum hydride in tetrahydrofuran at -78°C to afford 5-bromo-3- hydroxymethylpyridine as reported by Ashimori et al., Chem. Pharm. Bull. 38: 2446 (1990).
  • 5-bromonicotinic acid is esterified in the presence of sulfuric acid and ethanol, and the intermediate ester is reduced with sodium borohydride to yield 5 -bromo-3 -hydroxymethylpyridine, according to the techniques reported in C. F. Nutaitis et al., Org. Prep. AndProc. Int. 24: 143 (1992).
  • the 5-bromo-3- hydroxymethylpyridine can then be reacted with a number of different alkylating agents such as the p-toluenesulfonate ester of N-(tert-butoxycarbonyl)-N- methylethanolamine and others as previously described to provide the 5-bromo- pyridylmethoxy compounds such as (3-((5-bromo-3-pyridyl)methoxy)propyl) methylamine, (2-((5 -bromo-3 -pyridy l)methoxy)ethyl)methylamine, (3-((5-bromo-3- pyridyl)methoxy)- 1 -methylpropyl)methylamine, and (2-((5 -bromo-3 -pyridy 1) methoxy)-isopropyl)methylamine.
  • alkylating agents such as the p-toluenesulfonate ester of N-(tert-butoxy
  • Certain C-5-substituted pyridyl compounds of the present invention bearing a trifluoromethyl functionality at the C-5-pyridyl position can be prepared by a variety of methods.
  • 5-trifluoromethyl-3-pyridinemethanol can be alkylated with the p-toluenesulfonate ester of N-(tert-butoxycarbonyl)(butoxycarbonyl)-N- methylethanolamine using sodium hydride in N,N-dimethyformamide.
  • the protecting group of the resulting N-butoxycarbonyl-pyridinylmethoxyethanolamine compound can be removed by treatment with a strong acid such as trifluoroacetic acid to produce (2-((5-trifluoromethyl)-3-pyridyl)methoxy)ethyl)methylamine.
  • a strong acid such as trifluoroacetic acid
  • the requisite side chain, the tosylate of -butoxycarbonyl-protected N-methylethanolamine can be prepared according to the procedures set forth in J. Christoffers et al., Liebigs Ann./Recl. (7): 1353-1358 (1997).
  • the required 5-trifluoromethyl-3-pyridylcarbinol can be prepared from 5-trifluoromethyl-3-pyridinecarboxylic acid using methodology described by Ashimori et al., Chem. Pharm. Bull. 38: 2446 (1990).
  • a number of analogs substituted at C-5 of the pyridine ring in the aforementioned compounds can be prepared from the corresponding 5-bromo compound.
  • 5-amino substituted compounds and 5-alkylamino substituted compounds can be prepared from the corresponding 5-bromo compound using the general techniques described in C. Zwart, et al., Recueil Trav. Chim. Pays- Bas 74:1062 (1955).
  • 5-Alkoxy substituted analogs can be prepared from the corresponding 5-bromo compound using the general techniques described in D.L. Comins, et al., J. Org. Chem. 55:69 (1990) and H.J. Den Hertog et al., Reel. Trav. Chim.
  • 5-Ethynyl-substituted compounds can be prepared from the appropriate 5-bromo compound using the general techniques described in N.D.P. Cosford et al., J. Med. Chem. 39:3235 (1996).
  • the 5-ethynyl analogs can be converted into the corresponding 5-ethenyl, and subsequently the corresponding 5- ethyl analogs by successive catalytic hydrogenation reactions using techniques known to those skilled in the art of organic synthesis.
  • 5-Azido substituted analogs can be prepared from the corresponding 5-bromo compound by reaction with sodium azide in dimethylformamide.
  • 5-Alkylthio substituted analogs can be prepared from the corresponding 5-bromo compound by reaction with an appropriate alkylmercaptan in the presence of sodium using techniques known to those skilled in the art of organic synthesis.
  • a number of 5 -substituted analogs of the aforementioned compounds can be synthesized from the corresponding 5 -amino compounds via the 5-diazonium intermediate.
  • the other 5 -substituted analogs that can be produced from 5- diazonium intermediates are: 5-hydroxy analogs, 5-fiuoro analogs, 5-chloro analogs, 5-bromo analogs, 5-iodo analogs, 5-cyano analogs, and 5-mercapto analogs.
  • 5-hydroxy analogs can be prepared from the reaction of the corresponding 5-diazonium intermediate with water.
  • 5-Fluoro substituted analogs can be prepared from the reaction of the 5-diazonium intermediate with fluoroboric acid.
  • 5-Chloro substituted analogs can be prepared from the reaction of the 5-amino compound with sodium nitrite and hydrochloric acid in the presence of copper chloride.
  • 5-Cyano substituted analogs can be prepared from the reaction of the corresponding 5-diazonium intermediate with potassium copper cyanide.
  • 5 -Amino substituted analogs can also be converted to the corresponding 5-nitro analogs by reaction with fuming sulfuric acid and peroxide, according to the general techniques described in Y. Morisawa, J. Med. Chem. 20:129 (1977) for converting an aminopyridine to a nitropyridine.
  • 5-diazonium intermediates can also be used for the synthesis of mercapto-substituted analogs using the general techniques described in J.M. Hoffman et al., J. Med. Chem. 36:953 (1993).
  • the 5-mercapto substituted analogs can in turn be converted to the 5-alkylthio substituted analogs by reaction with sodium hydride and an appropriate alkyl bromide.
  • 5-Acylamido analogs of the aforementioned compounds can be prepared by reaction of the corresponding 5- amino compounds with an appropriate acid anhydride or acid chloride using techniques known to those skilled in the art of organic synthesis.
  • 5-hydroxy substituted analogs of the aforementioned compounds can be used to prepare corresponding 5-alkanoyloxy substituted compounds by reaction with the appropriate acid, acid chloride, or acid anhydride.
  • 5-cyano substituted analogs of the aforementioned compounds can be hydrolyzed using techniques known to those skilled in the art of organic synthesis to afford the corresponding 5-carboxamido substituted compounds. Further hydrolysis results in formation of the corresponding 5-carboxylic acid substituted analogs. Reduction of the 5-cyano substituted analogs with lithium aluminum hydride yields the corresponding 5-aminomethyl analog.
  • 5-acyl substituted analogs can be prepared from corresponding 5-carboxylic acid substituted analogs by reaction with an appropriate alkyl lithium.
  • 5-carboxylic acid substituted analogs of the aforementioned compounds can be converted to the corresponding ester by reaction with an appropriate alcohol.
  • 5-tosyloxymethyl substituted analogs of the aforementioned compounds can be converted to the corresponding 5 -methyl substituted compounds by reduction with lithium aluminum hydride.
  • Tosyloxymethyl substituted analogs of the aforementioned compounds can also be used to produce 5-alkyl substituted compounds via reaction with an alkyl lithium salt using techniques known to those skilled in the art of organic synthesis.
  • 5-hydroxy substituted analogs of the aforementioned compounds can be used to prepare 5-N-alkylcarbamoyloxy substituted compounds by reaction with N- alkylisocyanates.
  • 5-Amino substituted analogs of the aforementioned compounds can be used to prepare 5-N-alkoxycarboxamido substituted compounds by reaction with alkyl chloroformate esters, using techniques known to those skilled in the art of organic synthesis.
  • 2- and 6-methyl-3- pyridylmethoxyalkylamines such as methyl((2-(2-methyl-3-pyridylmethoxy)ethyl) amine and methyl((2-(6-methyl-3 -pyridy lmethoxy)ethyl)amine and methyl(l-methyl- 2-(2-methyl-3-pyridylmethoxy)ethyl)amine and methyl(l-methyl-2-(6-methyl-3- pyridylmethoxy)ethyl)amine using the methodology previously described.
  • the 4- substituted-3-pyridylmethoxyalkylamine-type compounds such as methyl((2-(4- methyl-3-pyridylmethoxy)ethyl)amine and methyl(l-methyl-2-(4-methyl-3- pyridylmethoxy)ethyl)amine can be prepared starting from 4-methyl-3- hydroxymethylpyridine.
  • the 4-methy 1-3 -hydroxymethylpyridme can be prepared starting from methyl 4-methy lnicotinate using methods similar to that described by C. F. Nutaitis et al., Org. Prep. And Proc. Int. 24: 143 (1992). The synthesis of methyl 4-methylnicotinate has been described by J. M. Bobbitt, et al., J. Org. Chem. 25:560 (1960).
  • pyridylmethoxyalkyl- cycloalkylamines such as (2-(l-methylpyrrolidin-2-yl)ethoxy)-3 -pyridy lmethane
  • 2-(2- chloroethyl)-l -methylpyrrolidine available from Aldrich Chemical Company
  • 2-(2- chloroethyl)-l -methylpyrrolidine can be used to alkylate 3-pyridylcarbinol using sodium hydride in tetrahydrofuran or N,N- dimethylformamide.
  • the p-toluenesulfonate ester of (2S)-l-(tert-butoxycarbonyl)-2- pyrrolidinemethanol can be used to alkylate 3-pyridylcarbinol using sodium hydride in tetrahydrofuran or N,N-dimethylformamide.
  • the butoxylcarbonyl-protecting group can be removed with strong acid such as trifluoroacetic acid or aqueous hydrochloric acid to give (2S)-3-pyridyl(pyrrolidin-2-ylmethoxy)methane.
  • the required p-toluenesulfonate ester of (2S)-l-(tert-butoxycarbonyl)-2- pyrrolidinemethanol can be prepared by treating (2S)-l-(tert-butoxycarbonyl)-2- pyrrolidinemethanol with p-toluenesulfonyl chloride in pyridine.
  • (2S)-2- pyrrolidinemethanol is available from Aldrich Chemical Company and can be butoxycarbonyl-protected by treatment with di-tert-butyl dicarbonate in tetrahydrofuran, followed by treatment with p-toluenesulfonyl chloride.
  • (2R)-3-pyridyl(pyrrolidin-2-ylmethoxy)methane can be prepared in an analogous manner starting from the p-toluenesulfonate ester of (2R)-1- (tert-butoxycarbonyl)-2-pyrrolidinemethanol.
  • (2R)-2-Pyrrolidinemethanol is available from Aldrich Chemical Company and can be butoxycarbonyl-protected by treatment with di-tert-butyl dicarbonate in tetrahydrofuran, followed by conversion to its tosylate.
  • (2S)-l-(tert-butoxycarbonyl)-2- pyrrolidinemethanol and (2R)-l-(tert-butoxycarbonyl)-2-pyrrolidinemethanol can be prepared according to the methods of D. A. Evans et al., J. Am. Chem. Soc. 101 : 371- 378 (1979) and B. D. Harris et al., Heterocycles 24: 1045-1060 (1986) starting from commercially available (Aldrich Chemical Company) D-proline and L-proline.
  • (2R)- and (2S)-3-pyridyl(pyrrolidin-2-ylmethoxy)methane can be N-methylated. Methylation methods similar to those described by M.
  • Compounds of the present invention which possess an arylmethoxy ether functionality with a chiral azacyclic fragment, such as ((2-azetidinyl)methoxy)(3- pyridyl)methane-type compounds can be prepared by a variety of synthetic methods.
  • the p-toluenesulfonate ester of a 3-pyridylcarbinol-type compound can be used to alkylate (2S)-l-(tert-butoxycarbonyl)-2-azetidinemethanol in the presence of a base such as sodium hydride in a solvent such as tetrahydrofuran or N,N-dimethylformamide.
  • the tert-butoxycarbonyl group can be removed with a strong acid such as trifluoroacetic acid or hydrochloric acid affording (2S)-((2- azetidinyl)methoxy)(3-pyridyl)methane-type compounds.
  • the requisite nonracemic compound, (2S)-l-tert-butoxycarbonyl)-2-azetidinemethanol can be prepared from (2S)-2-azetidinecarboxylic acid (commercially available from Aldrich Chemical Company) using the method of M. A. Abreo et al., J. Med. Chem. 39: 817-825 (1996).
  • the enantiomeric azetidinyl compound, (2R)-((2-azefidinyl)methoxy)(3- pyridyl)methane can be prepared in an analogous way by coupling the p- toluenesulfonate ester of a 3-pyridylcarbinol-type compound with (2R)-1- (benzyloxycarbonyl)-2-azetidinemethanol, followed by treatment with base, such as methanolic potassium hydroxide to remove the benzyloxycarbonyl protecting group.
  • base such as methanolic potassium hydroxide
  • arylmethoxyethers and possess a cyclic amine functionality can be prepared from an arylcarbinol, such as 3- pyridylcarbinol and hydroxylated cyclic amines using the general coupling method of O. Mitsunobu, Synthesis: 1 (1981).
  • (3 S)-((3 -pyridy l)methoxy) pyrrohdine can be synthesized by the coupling of 3-pyridylcarbinol and (3R)-N-(tert- butoxycarbonyl)-3-hydroxypyrrolidine in the presence of triphenylphosphine and diethyl azodicarboxylate in tetrahydrofuran.
  • the resulting intermediate can then be treated with a strong acid such as trifluoroacetic acid to remove the tert- butoxycarbonyl protecting group to produce (3S)-((3-pyridyl)methoxy)pyrrolidine.
  • the latter compound can be N-methylated to afford (3 S)-((3 -pyridy l)methoxy)-l - methylpyrrolidine.
  • Methylation methods employing aqueous formaldehyde and sodium cyanoborohydride as described by M. A. Abreo et al., J. Med. Chem. 39: 817- 825 (1996) can be used.
  • the N-protected starting material, (3R)-N-(tert- butoxycarbonyl)-3-hydroxypyrrolidine can be prepared from (R)-(+)-3-pyrrolidinol (commercially available from Aldrich Chemical Company) according to the general techniques described by P. G. Houghton et al., J. Chem. Soc.
  • 3- quinuclidinol available from Aldrich Chemical Company
  • 3- quinuclidinol can be converted to its p- toluenesulfonate and used to alkylate 3-pyridylcarbinol in the presence of sodium hydride and N,N-dimethylformamide to afford 3-((3-pyridyl)methoxy)quinuclidine.
  • Certain fused polycyclic aromatics can be used as starting materials to prepare compounds of the present invention which possess fused rings.
  • 3- quinolinecarbinol can be alkylated with the p-toluenesulfonate ester of N-(tert- butoxycarbonyl)( butoxycarbonyl)-N-methylethanolamine using sodium hydride in N,N-dimethyformamide.
  • the protecting group of the resulting N- butoxycarbonyl pyrimidinylmethoxyethanolamine compound can be removed by treatment with a strong acid such as trifluoroacetic acid to produce (2-((3-quinolyl)methoxy)ethyl) methylamine.
  • the requisite side chain, the tosylate of N- Butoxycarbonyl -protected N-methylethanolamine can be prepared according to the procedures set forth in J. Christoffers et al., Liebigs Ann./Recl. (7):1353-1358(1997).
  • the required 3- quinolinecarbinol can be prepared by the sodium borohydride reduction of 3- quinolinecarboxaldehyde (available from Aldrich Chemical Company).
  • Certain heteroaromatics can be used as starting materials to prepare compounds of the present invention.
  • 5-pyrimidinecarbinol can be alkylated with the p-toluenesulfonate ester of N-(tert-butoxycarbonyl) (butoxycarbonyl)-N-methylethanolamine using sodium hydride in N,N- dimethyformamide.
  • the protecting group of the resulting N-butoxycarbonyl- pyrimidinylmethoxyethanolamine compound can be removed by treatment with a strong acid such as trifluoroacetic acid to produce methyl(2-(pyrimidin-5- ylmethoxy)ethyl)amine.
  • the requisite side chain, the tosylate of N-butoxycarbonyl- protected N-methylethanolamine can be prepared according to the procedures set forth in j. Christoffers et al., Liebigs Ann./Recl. (7):1353-1358 (1997).
  • the required 5-pyrimidinecarbinol can be prepared from 5-pyrimidinecarboxylic acid using methodology similar to that described by C. F. Nutaitis et al., Org. Prep. And Proc. Int., 24: 143 (1992) or from ethyl 5-pyrimidinecarboxylate using methodolgy similar to that described by Ashimori et al., Chem. Pharm. Bull. 38: 2446 (1990).
  • the 5- pyrimidinecarboxylic acid can be prepared from 5-bromopyrimidine by lithiation and treatment with carbon dioxide as described by W. S. Messer, Jr. et al., Bioorg. Med. Chem. Lett. 2(8):781-786 (1992).
  • the ethyl 5-pyrimidinecarboxylate can be prepared from 5-bromopyrimidine using a palladium-catalyzed alkoxycarbonylation as described by R. A. Head et al., Tetrahedron Lett. 25(15):5939-5942 (1984).
  • Certain pyridylmethylthioalkylamine compounds can be prepared by the alkylation of 3-pyridinemethanethiol with the p-toluenesulfonate ester of N-(tert- butoxycarbonyl)-N-methylethanolamine using sodium hydride in N,N- dimethyformamide.
  • the protecting group of the resulting N-butoxycarbonyl- pyridylmethylthioethanolamine compound can be removed by treatment with a strong acid such as trifluoroacetic acid to produce (2-((3-pyridyl)methylthio)ethyl) methylamine.
  • the requisite side chain, the tosylate of N-butoxycarbonyl -protected N-methylethanolamine can be prepared according to the procedures set forth in J. Christoffers et al., Liebigs Ann./Recl. (7):1353-1358 (1997).
  • the 3- pyridinemethanethiol can be prepared from 3-(chloromethyl)pyridine hydrochloride (available from Aldrich Chemical Company) by heating with thiourea, followed by hydrolysis of the intermediate isothiourea with concentrated aqueous sodium hydroxide according to the methodology of T. J. Brown et al., J. Med. Chem. 35(20):3613-3624 (1992).
  • compounds of the present invention which possess a pyridylmethylthio ether functionality linked to a chiral azacyclic fragment, such as (2R)- and (2S)-3-pyridyl(pyrrolidin-2-ylmethoxy)methane and (2R)- and (2S)-((1- (methylpyrrolidin-2-yl)methoxy)-3-pyridylmethane can be prepared by a number of synthetic methods.
  • the p-toluenesulfonate ester of (2S)-l-(tert- butoxycarbonyl)-2-pyrrolidinemethanol (the synthesis of which has been previously described) can be used to alkylate 3-pyridinemethanethiol using sodium hydride in tetrahydrofuran or N,N-dimethylformamide.
  • the Butoxycarbonyl-protecting group can be removed with strong acid such as trifluoroacetic acid or aqueous hydrochloric acid to give (2S)-(3-pyridyl)(pyrrolidin-2-ylmethylthio)methane.
  • the latter compound can be N-methylated employing aqueous formaldehyde and sodium cyanoborohydride as using methodology similar to that described by M.A. Abreo et al., J. Med. Chem. 39: 817-825 (1996) to produce (2S)-(3-pyridyl)((l- methylpyrrolidin-2-yl)methylthio)methane.
  • the present invention relates to a method for providing prevention of a condition or disorder to a subject susceptible to such a condition or disorder, and for providing treatment to a subject suffering therefrom.
  • the method comprises administering to a patient an amount of a compound effective for providing some degree of prevention of the progression of a CNS disorder (i.e., provide protective effects), amelioration of the symptoms of a CNS disorder, and amelioration of the recurrence of a CNS disorder.
  • the method involves administering an effective amount of a compound selected from the general formulae which are set forth hereinbefore.
  • the present invention relates to a pharmaceutical composition incorporating a compound selected from the general formulae which are set forth hereinbefore.
  • Optically active compounds can be employed as racemic mixtures or as enantiomers.
  • the compounds can be employed in a free base form or in a salt form (e.g., as pharmaceutically acceptable salts).
  • suitable pharmaceutically acceptable salts include inorganic acid addition salts such as hydrochloride, hydrobromide, sulfate, phosphate, and nitrate; organic acid addition salts such as acetate, galactarate, propionate, succinate, lactate, glycolate, malate, tartrate, citrate, maleate, fumarate, methanesulfonate, p-toluenesulfonate, and ascorbate; salts with acidic amino acid such as aspartate and glutamate; alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as magnesium salt and calcium salt; ammonium salt; organic basic salts such as trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, and N,N'- dibenzylethylenediamine salt;
  • the salts may be in some cases hydrates or ethanol solvates.
  • Representative salts are provided as described in U.S. Patent Nos. 5,597,919 to Dull et al., 5,616,716 to Dull et al. and 5,663,356 to Ruecroft et al., the disclosures of which are incorporated herein by reference in their entirety.
  • Compounds of the present invention are useful for treating those types of conditions and disorders for which other types of nicotinic compounds have been proposed as therapeutics. See, for example, Williams et al. DN&P 7(4):205-227 (1994), Arneric et al., CNS Drug Rev. 1(1): 1-26 (1995), Arneric et al, Exp. Opin.
  • Compounds of the present invention can be used as analgesics, to treat ulcerative colitis, to treat a variety of neurodegenerative diseases, and to treat convulsions such as those that are symtematic of epilepsy.
  • CNS disorders which can be treated in accordance with the present invention include presenile dementia (early onset Alzheimer's disease), senile dementia (dementia of the Alzheimer's type), HIV-dementia, multiple cerebral infarcts, Parkinsonism including Parkinson's disease, Pick's disease, Huntington's chorea, tardive dyskinesia, hyperkinesia, mania, attention deficit disorder, anxiety, depression, mild cognitive impairment, dyslexia, schizophrenia and Tourette's syndrome.
  • Compounds of the present invention also can be used to treat conditions such as syphillis and Creutzfeld- Jakob disease.
  • the pharmaceutical composition also can include various other components as additives or adjuncts.
  • exemplary pharmaceutically acceptable components or adjuncts which are employed in relevant circumstances include antioxidants, free radical scavenging agents, peptides, growth factors, antibiotics, bacteriostatic agents, immunosuppressives, anticoagulants, buffering agents, anti-inflammatory agents, antipyretics, time release binders, anaesthetics, steroids, vitamins, minerals and corticosteroids.
  • Such components can provide additional therapeutic benefit, act to affect the therapeutic action of the pharmaceutical composition, or act towards preventing any potential side effects which may be posed as a result of administration of the pharmaceutical composition.
  • a compound of the present invention can be employed as part of a pharmaceutical composition with other compounds intended to prevent or treat a particular disorder.
  • the manner in which the compounds are administered can vary.
  • the compounds can be administered by inhalation (e.g., in the form of an aerosol either nasally or using delivery articles of the type set forth in U.S. Patent No. 4,922,901 to Brooks et al., the disclosure of which is incorporated herein in its entirety); topically (e.g., in lotion form); orally (e.g., in liquid form within a solvent such as an aqueous or non-aqueous liquid, or within a solid carrier); intravenously (e.g., within a dextrose or saline solution); as an infusion or injection (e.g., as a suspension or as an emulsion in a pharmaceutically acceptable liquid or mixture of liquids); intrathecally; intracerebro ventricularly; or transdermally (e.g., using a transdermal patch).
  • inhalation e.g., in the form of an aerosol either nasally or using delivery articles of the type set forth in U.
  • each compound in the form of a pharmaceutical composition or formulation for efficient and effective administration.
  • exemplary methods for administering such compounds will be apparent to the skilled artisan.
  • the compounds can be administered in the form of a tablet, a hard gelatin capsule or as a time release capsule.
  • the compounds can be delivered transdermally using the types of patch technologies available from Novartis and Alza Corporation.
  • the administration of the pharmaceutical compositions of the present invention can be intermittent, or at a gradual, continuous, constant or controlled rate to a warm-blooded animal, (e.g., a mammal such as a mouse, rat, cat, rabbit, dog, pig, cow, or monkey); but advantageously is preferably administered to a human being.
  • a warm-blooded animal e.g., a mammal such as a mouse, rat, cat, rabbit, dog, pig, cow, or monkey
  • the time of day and the number of times per day that the pharmaceutical formulation is administered can vary.
  • Administration preferably is such that the active ingredients of the pharmaceutical formulation interact with receptor sites within the body of the subject that effect the functioning of the CNS.
  • administering preferably is such so as to optimize the effect upon those relevant receptor subtypes which have an effect upon the functioning of the CNS, while minimizing the effects upon muscle- type receptor subtypes.
  • Other suitable methods for administering the compounds of the present invention are described in U.S. Patent No. 5,604,231 to Smith et al.
  • an effective amount of compound is an amount sufficient to pass across the blood-brain barrier of the subject, to bind to relevant receptor sites in the brain of the subject, and to activate relevant nicotinic receptor subtypes (e.g., provide neurotransmitter secretion, thus resulting in effective prevention or treatment of the disorder).
  • an effective amount of compound is an amount sufficient to pass across the blood-brain barrier of the subject, to bind to relevant receptor sites in the brain of the subject, and to activate relevant nicotinic receptor subtypes (e.g., provide neurotransmitter secretion, thus resulting in effective prevention or treatment of the disorder).
  • Prevention of the disorder is manifested by delaying the onset of the symptoms of the disorder.
  • Treatment of the disorder is manifested by a decrease in the symptoms associated with the disorder or an amelioration of the reoccurrence of the symptoms of the disorder.
  • the effective dose can vary, depending upon factors such as the condition of the patient, the severity of the symptoms of the disorder, and the manner in which the pharmaceutical composition is administered.
  • the effective dose of typical compounds generally requires administering the compound in an amount sufficient to activate relevant receptors to effect neurotransmitter (e.g., dopamine) release but the amount should be insufficient to induce effects on skeletal muscles and ganglia to any significant degree.
  • the effective dose of compounds will of course differ from patient to patient but in general includes amounts starting where CNS effects or other desired therapeutic effects occur, but below the amount where muscular effects are observed.
  • the effective dose of compounds generally requires administering the compound in an amount of less than 5 mg/kg of patient weight.
  • the compounds of the present invention are administered in an amount from less than about 1 mg/kg patent weight, and usually less than about 100 ug/kg of patient weight, but frequently between about 10 ug to less than 100 ug/kg of patient weight.
  • the effective dose is less than 5 mg/kg of patient weight; and often such compounds are administered in an amount from 50 ug to less than 5 mg/kg of patient weight.
  • the foregoing effective doses typically represent that amount administered as a single dose, or as one or more doses administered over a 24 hour period.
  • the effective dose of typical compounds generally requires administering the compound in an amount of at least about 1 , often at least about 10, and frequently at least about 25 ug/ 24 hr./ patient.
  • the effective dose of typical compounds requires administering the compound which generally does not exceed about 500, often does not exceed about 400, and frequently does not exceed about 300 ug/ 24 hr./ patient.
  • administration of the effective dose is such that the concentration of the compound within the plasma of the patient normally does not exceed 500 ng/ml, and frequently does not exceed 100 ng/ml.
  • the compounds useful according to the method of the present invention have the ability to pass across the blood-brain barrier of the patient. As such, such compounds have the ability to enter the central nervous system of the patient.
  • the log P values of typical compounds, which are useful in carrying out the present invention are generally greater than about —0.5, often are greater than about 0, and frequently are greater than about 0.5.
  • the log P values of such typical compounds generally are less than about 3, often are less than about 2, and frequently are less than about 1.
  • Log P values provide a measure of the ability of a compound to pass across a diffusion barrier, such as a biological membrane. See, Hansch, et al., J. Med. Chem. 11 :1 (1968).
  • the compounds useful according to the method of the present invention have the ability to bind to, and in most circumstances, cause activation of, nicotinic dopaminergic receptors of the brain of the patient. As such, such compounds have the ability to express nicotinic pharmacology, and in particular, to act as nicotinic agonists.
  • the receptor binding constants of typical compounds useful in carrying out the present invention generally exceed about 0.1 nM, often exceed about 1 nM, and frequently exceed about 10 nM.
  • the receptor binding constants of certain compounds are less than about 100 uM, often are less than about 10 uM and frequently are less than about 5 uM; and of preferred compounds generally are less than about 2.5 uM, sometimes are less than about 1 uM, and can be less than about 100 nM.
  • Receptor binding constants provide a measure of the ability of the compound to bind to half of the relevant receptor sites of certain brain cells of the patient. See, Cheng, et al., Biochem. Pharmacol. 22:3099 (1973).
  • the compounds useful according to the method of the present invention have the ability to demonstrate a nicotinic function by effectively activating neurotransmitter secretion from nerve ending preparations (i.e., synaptosomes). As such, such compounds have the ability to activate relevant neurons to release or secrete acetylcholine, dopamine, and other neurotransmitter s.
  • typical compounds useful in carrying out the present invention provide for the activation of dopamine secretion in amounts of at least one third, typically at least about 10 times less, frequently at least about 100 times less, and sometimes at least about 1,000 times less, than those required for activation of muscle-type nicotinic receptors.
  • Certain compounds of the present invention can provide secretion of dopamine in an amount which is comparable to that elicited by an equal molar amount of (S)-(-)-nicotine.
  • the compounds of the present invention when employed in effective amounts in accordance with the method of the present invention, are selective to certain relevant nicotinic receptors, but do not cause significant activation of receptors associated with undesirable side effects at concentrations at least greater than those required for activation of dopamine release.
  • a particular dose of compound resulting in prevention and/or treatment of a CNS disorder is essentially ineffective in eliciting activation of certain ganglia-type nicotinic receptors at concentration higher than 5 times, preferably higher than 100 times, and more preferably higher than 1,000 times, than those required for activation of dopamine release.
  • Compounds of the present invention when employed in effective amounts in accordance with the method of the present invention, are effective towards providing some degree of prevention of the progression of CNS disorders, amelioration of the symptoms of CNS disorders, an amelioration to some degree of the reoccurrence of CNS disorders.
  • effective amounts of those compounds are not sufficient to elicit any appreciable side effects, as demonstrated by increased effects relating to skeletal muscle.
  • administration of certain compounds of the present invention provides a therapeutic window in which treatment of certain CNS disorders is provided, and certain side effects are avoided. That is, an effective dose of a compound of the present invention is sufficient to provide the desired effects upon the CNS, but is insufficient (i.e., is not at a high enough level) to provide undesirable side effects.
  • effective administration of a compound of the present invention resulting in treatment of CNS disorders occurs upon administration of less than 1/5, and often less than 1/10 that amount sufficient to cause certain side effects to any significant degree.
  • the pharmaceutical compositions of the present invention can be employed to prevent or treat certain other conditions, diseases and disorders.
  • diseases and disorders include inflammatory bowel disease, acute cholangitis, aphteous stomatitis, arthritis (e.g., rheumatoid arthritis and ostearthritis), neurodegenerative diseases, cachexia secondary to infection (e.g., as occurs in AIDS, AIDS related complex and neoplasia), as well as those indications set forth in PCT WO 98/25619.
  • the pharmaceutical compositions of the present invention can be employed in order to ameliorate may of the symptoms associated with those conditions, diseases and disorders.
  • compositions of the present invention can be used in treating genetic diseases and disorders, in treating autoimmune disorders such as lupus, as anti-infectious agents (e.g, for treating bacterial, fungal and viral infections, as well as the effects of other types of toxins such as sepsis), as anti-inflammatory agents (e.g., for treating acute cholangitis, aphteous stomatitis, asthma, and ulcerative colitis), and as inhibitors of cytokines release (e.g., as is desirable in the treatment of cachexia. inflammation, neurodegenerative diseases, viral infection, and neoplasia),
  • the compounds of the present invention can also be used as adjunct therapy in combination with existing therapies in the management of the aforementioned types of diseases and disorders.
  • administration preferably is such that the active ingredients of the pharmaceutical formulation act to optimize effects upon abnormal cytokine production, while minimizing effects upon receptor subtypes such as those that are associated with muscle and ganglia.
  • Administration preferably is such that active ingredients interact with regions where cytokine production is affected or occurs.
  • compounds of the present invention are very potent (i.e., affect cytokine production and/or secretion at very low concentrations), and are very efficacious (i.e., significantly inhibit cytokine production and/or secretion to a relatively high degree).
  • Effective doses are most preferably at very low concentrations, where maximal effects are observed to occur. Concentrations, determined as the amount of compound per volume of relevant tissue, typically provide a measure of the degree to which that compound affects cytokine production. Typically, the effective dose of such compounds generally requires administering the compound in an amount of much less than 100 ug/kg of patient weight, and even less than lOu/kg of patient weight. The foregoing effective doses typically represent the amount administered as a single dose, or as one or more doses administered over a 24 hour period.
  • the effective dose of typical compounds generally requires administering the compound in an amount of at least about 1, often at least about 10, and frequently at least about 25 ug / 24 hr. / patient.
  • the effective dose of typical compounds requires administering the compound which generally does not exceed about 1, often does not exceed about 0.75, often does not exceed about 0.5, frequently does not exceed about 0.25 mg / 24 hr. / patient.
  • administration of the effective dose is such that the concentration of the compound within the plasma of the patient normally does not exceed 500 pg/ml, often does not exceed 300 pg/ml, and frequently does not exceed 100 pg/ml.
  • compounds of the present invention When employed in such a manner, compounds of the present invention are dose dependent, and as such, cause inhibition of cytokine production and/or secretion when employed at low concentrations but do not exhibit those inhibiting effects at higher concentrations. Compounds of the present invention exhibit inhibitory effects upon cytokine production and/or secretion when employed in amounts less than those amounts necessary to elicit activation of relevant nicotinic receptor subtypes to any significant degree.
  • the 3-chloro-l-(3-pyridylmethoxy)propane (0.360 g, 1.96 mmol) was dissolved in methanol (25 mL) and added to a 40 wt% aqueous solution of methylamine (50 mL) in a heavy-walled glass pressure-tube apparatus. The tube was sealed and the mixture was stirred and heated at 100°C (oil bath temperature) for 4 h. After cooling, the mixture was concentrated by rotary evaporation. Saturated NaCl solution (25 mL) was added to the residue, the pH was adjusted to 1 with 10% HC1 solution and the solution was extracted with CHC1 (3 x 20 mL) to remove impurities.
  • the pH of the aqueous phase was adjusted to 6, and impurities were extracted with ether (3 x 15 mL).
  • the aqueous layer was basified to pH 10 with 10% NaOH solution and extracted with chloroform (4 x 15 mL).
  • the combined chloroform extracts were dried (Na 2 SO 4 ), filtered, and concentrated by rotary evaporation to a residue that was dried briefly under high vacuum to give 52.8 mg (15.0%) of a dark brown oil.
  • Binding of the compounds to relevant receptor sites was determined in accordance with the techniques described in U.S. Patent No. 5,597,919 to Dull et al. Inhibition constants (Ki values), reported in nM, were calculated from the IC 50 values using the method of Cheng et al., Biochem, Pharmacol. 22:3099 (1973). Low binding constants indicate that the compounds of the present invention exhibit good high affinity binding to certain CNS nicotinic receptors. The compound of Example 1 exhibits a Ki of 2272 nM.
  • Example 3 Neurotransmitter Release From Brain Synaptosomes
  • Neurotransmitter release was measured using techniques similar to those previously published (Bencherif M, et al.:. JPET 279: 1413-1421, 1996).
  • Rat brain synaptosomes were prepared as follows: Female Sprague Dawley rats (100-200 g) were killed by decapitation after anesthesia with 70% C0 . Brains are dissected, and hippocampus, striatum, and thalamus isolated, and homogenized in 0.32 M sucrose containing 5 mM HEPES pH 7.4 using a glass/glass homogenizer. The tissue was then centrifuged for 1000 x g for 10 minutes and the pellet discarded. The supernatant was centrifuged at 12000 x g for 20 minutes.
  • the resultant pellet was re-suspended in perfusion buffer (128 mM NaCl, 1.2 mM KH2PO4, 2.4 mM KCl, 3.2 mM CaCl 2 , 1.2 mM MgSO 4 , 25 mM HEPES, 1 mM Ascorbic acid, 0.01 mM pargyline HC1 and 10 mM glucose pH 7.4) and centrifuged for 15 minutes at 25000 x g. The final pellet was resuspended in perfusion buffer and placed in a water bath (37°C) for 10 minutes.
  • Radiolabeled neurotransmitter is added (30 uL 3 H DA, 20 L H NE, 10 uL H glutamate) to achieve a final concentration of 100 nM, vortexed and placed in a water bath for additional 10 minutes. Tissue-loaded filters is placed onto 11 -mm diameter Gelman A/E filters on an open-air support. After a 10-minute wash period, fractions are collected to establish the basal release and agonist applied in the perfusion stream. Further fractions were collected after agonist application to reestablish the baseline. The perfusate was collected directly into scintillation vials and released radioactivity was quantified using conventional liquid scintillation techniques.
  • Release of neurotransmitter was determined in the presence of 10 uM of various ligands and was expressed as a percentage of release obtained with a concentration of 10 uM (S)-(-)-nicotine or 300 uM TMA resulting in maximal effects.
  • the compound of Example 1 exhibits an E max of 42 percent.
  • the determination of the interaction of the compounds with muscle receptors was carried out in accordance with the techniques described in U.S. Patent No. 5,597,919 to Dull et al.
  • the maximal activation for individual compounds (E max ) was determined as a percentage of the maximal activation induced by (S)-(-)-nicotine.
  • Reported E max values represent the amount released relative to (S)-(-)-nicotine on a percentage basis.
  • Low E max values at muscle-type receptors indicate that the compounds of the present invention do not induce activation of muscle-type receptors.
  • Such preferable compounds have the capability to activate human CNS receptors without activating muscle-type nicotinic acetylcholine receptors.
  • a therapeutic window for utilization in the treatment of CNS disorders That is, at certain levels the compounds show CNS effects to a significant degree but do not show undesirable muscle effects to any significant degree.
  • the compound of Example 1 exhibits an E max of 21 percent.
  • the determination of the interaction of the compounds with ganglionic receptors was carried out in accordance with the techniques described in U.S. Patent No. 5,597,919 to Dull et al.
  • the maximal activation for individual compounds (E max ) was determined as a percentage of the maximal activation induced by (S)-(-)-nicotine.
  • Reported E max values represent the amount released relative to (S)-(-)-nicotine on a percentage basis.
  • Low E max values at ganglia-type receptors indicate that the compounds of the present invention do not induce activation of ganglia-type receptors.
  • Such preferable compounds have the capability to activate human CNS receptors without activating ganglia-type nicotinic acetylcholine receptors.
  • a therapeutic window for utilization in the treatment of CNS disorders That is, at certain levels the compounds show CNS effects to a significant degree but do not show certain undesirable side effects to any significant degree.
  • the compound of Example 1 exhibits an E max of

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Abstract

On traite des patients susceptibles de souffrir ou souffrant de pathologies et de troubles, tels que des troubles du système nerveux central, en leur administrant des composés arylalkyloxyalkylamines et arylalkylthioalkylamines, qui comprennent des arylméthoxyalkylamines et des arylméthylthioalkylamines, tels que des pyridylméthoxyalkylamines et des pyridylméthylthio alkylamines. Des composés de l'invention comprennent méthyl(3-(3-pyridylméthoxy)propyl)amine, 3-pyridyl(pyrrolidin-2-ylméthoxy)méthane, méthyl(1-méthyl-2-(3-pyridylméthoxy)éthyl)amine, (3-((3-pyridyl)méthoxy)propyl)diméthylamine, (2-((5-bromo-3-pyridyl)méthoxy)éthyl)méthylamine, méthyl(2-((t-méthoxy-3-pyridly)méthoxy)éthyl)amine, (2-((3-quinolyl) méthoxy)éthyl)méthylamine, méthyl(2-(pyrimidin-5-ylméthoxy)éthyl)amine, 3-((3-pyridyl)méthoxy)quinuclidine, (3-pyridyl)quinuclidin-2-ylméthoxy)méthane, (3-pyridyl)pyrrolidin-2-ylméthylthio)méthane et (2-((3-pyridyl)méthylthio)éthyl) méthylamine.
PCT/US2000/017978 1999-08-31 2000-06-30 Arylalkyloxyalkylamines et arylalkylthioalkylamines, compositions pharmaceutiques les contenant et leur utilisation en tant qu'inhibiteurs des recepteurs cholinergiques nicotiniques WO2001016107A1 (fr)

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EP00945006A EP1212301A1 (fr) 1999-08-31 2000-06-30 Arylalkyloxyalkylamines et arylalkylthioalkylamines, compositions pharmaceutiques les contenant et leur utilisation en tant qu'inhibiteurs des recepteurs cholinergiques nicotiniques
CA002383307A CA2383307A1 (fr) 1999-08-31 2000-06-30 Arylalkyloxyalkylamines et arylalkylthioalkylamines, compositions pharmaceutiques les contenant et leur utilisation en tant qu'inhibiteurs des recepteurs cholinergiques nicotiniques
AU59007/00A AU5900700A (en) 1999-08-31 2000-06-30 Arylalkyloxyalkylamines and arylalkylthioalkylamines, pharmaceutical compositions containing them and their use as inhibitors of nicotinic cholinergic receptors

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004009599A1 (fr) * 2002-07-19 2004-01-29 Targacept, Inc. Composes heteroaromatiques olefiniques azacycliques a cinq elements, compositions pharmaceutiques contenant lesdits composes et leur utilisation comme inhibiteurs des recepteurs nicotiniques cholinergiques
US8445684B2 (en) 2008-10-14 2013-05-21 PsycoGenics Inc. Nicotinic acetylcholine receptor ligands and the uses thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999032117A1 (fr) * 1997-12-22 1999-07-01 Sibia Neurosciences, Inc. Nouveaux composes pyridine substitues utiles en tant que modulateurs des recepteurs de l'acetylcholine
WO1999065876A1 (fr) * 1998-06-16 1999-12-23 R.J. Reynolds Tobacco Company Amines olefiniques a substitution aryle et leur utilisation comme agonistes de recepteurs cholinergiques
WO2000034276A1 (fr) * 1998-12-11 2000-06-15 R.J. Reynolds Tobacco Company Derives a tete de pont pyridyle et leurs analogues, compositions pharmaceutiques et leur utilisation comme inhibiteurs des recepteurs cholinergiques nicotiniques

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999032117A1 (fr) * 1997-12-22 1999-07-01 Sibia Neurosciences, Inc. Nouveaux composes pyridine substitues utiles en tant que modulateurs des recepteurs de l'acetylcholine
WO1999065876A1 (fr) * 1998-06-16 1999-12-23 R.J. Reynolds Tobacco Company Amines olefiniques a substitution aryle et leur utilisation comme agonistes de recepteurs cholinergiques
WO2000034276A1 (fr) * 1998-12-11 2000-06-15 R.J. Reynolds Tobacco Company Derives a tete de pont pyridyle et leurs analogues, compositions pharmaceutiques et leur utilisation comme inhibiteurs des recepteurs cholinergiques nicotiniques

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004009599A1 (fr) * 2002-07-19 2004-01-29 Targacept, Inc. Composes heteroaromatiques olefiniques azacycliques a cinq elements, compositions pharmaceutiques contenant lesdits composes et leur utilisation comme inhibiteurs des recepteurs nicotiniques cholinergiques
US8445684B2 (en) 2008-10-14 2013-05-21 PsycoGenics Inc. Nicotinic acetylcholine receptor ligands and the uses thereof

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