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WO2000071520A2 - Compositions pharmaceutiques et methodes d'utilisation - Google Patents

Compositions pharmaceutiques et methodes d'utilisation Download PDF

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Publication number
WO2000071520A2
WO2000071520A2 PCT/US2000/011256 US0011256W WO0071520A2 WO 2000071520 A2 WO2000071520 A2 WO 2000071520A2 US 0011256 W US0011256 W US 0011256W WO 0071520 A2 WO0071520 A2 WO 0071520A2
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WIPO (PCT)
Prior art keywords
methyl
amine
pyridyloxy
pyrimidin
pyrimidine
Prior art date
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PCT/US2000/011256
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English (en)
Other versions
WO2000071520A3 (fr
Inventor
Gary Maurice Dull
Erin E. Reich
Jared Miller Wagner
Balwinder Singh Bhatti
Michael B. Consilvio
Original Assignee
Targacept, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US09/317,327 external-priority patent/US20010031771A1/en
Application filed by Targacept, Inc. filed Critical Targacept, Inc.
Priority to MXPA01012202A priority Critical patent/MXPA01012202A/es
Priority to EP00928437A priority patent/EP1185513A2/fr
Priority to CA002373789A priority patent/CA2373789A1/fr
Priority to KR1020017015045A priority patent/KR20020010670A/ko
Priority to BR0011534-7A priority patent/BR0011534A/pt
Priority to JP2000619777A priority patent/JP2003500393A/ja
Priority to AU46678/00A priority patent/AU4667800A/en
Publication of WO2000071520A2 publication Critical patent/WO2000071520A2/fr
Publication of WO2000071520A3 publication Critical patent/WO2000071520A3/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
    • C07D213/60—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
    • C07D213/70—Sulfur 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/27—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups
    • C07C205/35—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C205/36—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton to carbon atoms of the same non-condensed six-membered aromatic ring or to carbon atoms of six-membered aromatic rings being part of the same condensed ring system
    • C07C205/37—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by etherified hydroxy groups having nitro groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton to carbon atoms of the same non-condensed six-membered aromatic ring or to carbon atoms of six-membered aromatic rings being part of the same condensed ring system the oxygen atom of at least one of the etherified hydroxy groups being further bound to an acyclic carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
    • C07C217/14—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring
    • C07C217/16—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring not being further substituted
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
    • C07C217/14—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring
    • C07C217/18—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted
    • C07C217/20—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted by halogen atoms, by trihalomethyl, nitro or nitroso groups, or by singly-bound oxygen 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
    • 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
    • C07D239/28—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/34—One oxygen atom
    • 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
    • C07D239/28—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/38—One sulfur atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring 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 atoms of the carbocyclic ring
    • C07D317/64—Oxygen atoms

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. ). Med. 330:81 1-81 5 (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 are 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 al., /. Neurochem. 50:1 123 (1988); Sandor et al., Brain 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 aryloxyalkylamines, including pyridyloxylalkylamines and phenoxyalkylamines.
  • Exemplary compounds include dimethyl(2-(3-pyridyloxy)ethylamine, dimethyl(4-(3-pyridyloxy)butyl)amine, 2-(3- pyridyloxy)ethylamine, 4-(3-pyridyloxy)butylamine, methyl (3-(5-methoxy-3- pyridyloxy)propyl)amine, ethyl(3-(3-pyridyloxy)propyl)amine, methyl(2-(3- pyridyloxy)ethyl)amine, methyl(3-(6-methyl(3-pyridyloxy))propyl)amine, (3-(3-methoxyphenoxy)propyl)methylamine, (3-(5-chloro(3-pyridyloxy
  • the present invention also relates to prodrug derivatives of the compounds of the present invention.
  • 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 I:
  • each of X and X' are individually nitrogen, N-O 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 ); and m is an integer and n is an integer such that the sum of m plus n is 1 , 2, 3, 4, 5, 6, 7, or 8, preferably is 1 , 2, or 3, and more preferably is 2 or 3, and most preferably 3.
  • B' is oxygen or sulfur, but most preferably is oxygen.
  • Z' and Z" individually represent hydrogen or lower alkyl (e.g., straight chain or branched alkyl including G-C ⁇ , preferably Ci-Cs, such as methyl, ethyl, or isopropyl), Z 1 and Z" individually represent hydrogen, alkyl (e.g., straight chain or branched alkyl including Ci-Cs, preferably C1-C5, such as methyl, ethyl, or isopropyl), substituted alkyl, acyl, alkoxycarbonyl, or aryloxycarbonyl; and preferably at least one of Z 1 and Z" is hydrogen or both of Z 1 and Z" are hydrogen, and most preferably Z 1 is hydrogen and Z" is methyl.
  • alkyl e.g., straight chain or branched alkyl including G-C ⁇ , preferably Ci-Cs, such as methyl, ethyl, or isopropyl
  • Z 1 and Z" individually represent hydrogen, alkyl (e.g., straight
  • Z 1 is hydrogen and Z" represents a ring structure (cycloalkyl, heterocyclyl or aryl), such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, quinuclidinyl, pyridinyl, quinolinyl, pyrimidinyl, phenyl, benzyl, thiazolyl or oxazolyl (where any of the foregoing can be suitably substituted with at least one substituent group, such as alkyl, alkoxyl, halo, or amino substituents); alternatively Z' is hydrogen and Z" is propargyl; alternatively Z 1 , Z", and the associated nitrogen atom can form a ring structure such as aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, 2- imino-2,3-dihydride,
  • E, E', E” and E 1 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 Ci-C ⁇ , preferably Ci-Cs, such as methyl, ethyl, or isopropyl) or halo substituted lower alkyl (e.g., straight chain or branched alkyl including Ci-Cs, preferably C1-C5, such as trifluoromethyl or trichloromethyl).
  • a suitable non- hydrogen substituent e.g., alkyl, substituted alkyl, halo substituted alkyl,
  • E, E 1 , E” and E 1 " are hydrogen, or at least one of E, E 1 , E” and E 1 " is non-hydrogen and the remaining E, E 1 , E” and E 1 " are hydrogen.
  • E and E' or E” and E 1 " and their associated carbon atom can combine to form a ring structure such as cyclopentyl, cyclohexyl or cycloheptyl; or E 1 " and E 1 (when located on immediately adjacent carbon atoms) and their associated carbon atoms can combine to form a ring structure such as cyclopentyl, cyclohexyl or cycloheptyl.
  • compounds of the present invention have chiral centers, and the present invention relates to racemic mixtures of such compounds as well as enamiomeric compounds.
  • X is nitrogen; for other compounds X' is nitrogen or N-O; and for other compounds X and X' both are nitrogen. Most preferably, X' is nitrogen.
  • Adjacent substituents of A, A 1 or A" 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.
  • X' is C-NR'R", C-OR' or C-N0 2 , more preferably C-NH , C-NHCH or C-N(CH 3 ) 2 , with C-NH being most preferred.
  • substituent species when X is carbon bonded to a substituent species, it is preferred that the substituent species is H, Br or OR', where R' preferably is benzyl, methyl, ethyl, isopropyl, isobutyl or tertiary butyl.
  • A, A 1 , A" and the substituents of either X or X' can include H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, heterocyclyl, substituted heterocyclyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, alkylaryl, substituted alkylaryl, arylalkyl and substituted arylalkyl functionalities.
  • 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).
  • a cycloalkyl funtionality e.g., cyclopropyl cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, and quinuclidinyl.
  • 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).
  • substituent groups such as alkyl, halo, or amino substituents.
  • Other representative aromatic ring systems are set forth in Gibson et al., /. Med. Chem. 39:4065 (1996).
  • X and X' represent a carbon atom bonded to a substituent species, that substituent species often has a sigma m value which is between about -0.3 and about 0.75, and frequently between about -0.25 and about 0.6. In certain circumstances the substituent species is characterized as having a sigma m value not equal to 0.
  • A, A' and A" individually represent those species described as substituent species to the aromatic carbon atom previously described for X and X'; and usually include hydrogen, halo (e.g., F, CI, Br, or I), alkyl (e.g., lower straight chain or branched C ⁇ -8 alkyl, but preferably methyl or ethyl), or NX"X'" where X" and X'" are individually hydrogen or lower alkyl, including Ci-Cs, preferably Ci-Cs alkyl.
  • A is hydrogen
  • A' is hydrogen
  • normally A" is hydrogen.
  • both A and A' are hydrogen; sometimes A and A' are hydrogen, and A" is amino, methyl or ethyl; and often A, A' and A" are all hydrogen.
  • certain compounds can be optically active.
  • the selection of E, E', E" and E'” is such that up to about 4, and frequently up to 3, and usually 0, 1 or 2, of the substituents designated as E, E', E" and E'" are non-hydrogen substituents (i.e., substituents such as lower alkyl or halo-substituted lower alkyl).
  • X is CH, CBr or COR. Most preferably, X' is nitrogen.
  • alkyl refers to straight chain or branched alkyl radicals including G-Cs, preferably Ci-Cs, 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 G-Cs, preferably G-Cs 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 cycloalkyl
  • One representative compound is (3-(3-pyridyloxy)propyl)amine, for which X is CH, X' is N, B' is O, n is 0, m is 3, and A, A' f A", E, E', Z' and Z" are each H.
  • One representative compound is (3-(5-bromo-(3- pyridyloxy)propyl)methylamine, for which X is C-Br, X' is N, B' is O, n is 0, m is 3, A, A', A", E, E' and Z' are each H, and Z" is methyl.
  • One representative compound is (1-methyl-3-(3-pyridyloxy)propyl)methylamine, for which X is CH, X' is N, B' is O, n is 1 , m is 2, A, A', A", E, E', E" and Z' are each H, and E'" and Z" are methyl.
  • One representative compound is (3-(5-ethoxy-(3- pyridyloxy)propyl)methylamine, for which X is C-OCH CH 3 , X' is N, B' is O, n is 0, m is 3, A, A', A", E, E' and Z' are each H, and Z" is methyl.
  • One representative compound is (3-(6-methyl-(3-pyridyloxy)propyl)methylamine, for which X is CH, X' is N, B' is O, n is 0, m is 3, A, A', E, E' and Z' are each H, and N'and Z" each are methyl.
  • One representative compound is (3-(5-chloro-(3- pyridyloxy)propyl)methylamine, for which X is C-Cl, X' is N, B' is O, n is 0, m is 3, A, A', A", E, E' and Z' are each H, and Z" is methyl.
  • One representative compound is (3-(2-bromo(3-pyridyloxy)propyl)methylamine, for which X is CH, X' is N, B' is O, n is 0, m is 3, A is Br, A', A", E, E' and Z' are each H, and Z" is methyl.
  • One representative compound is (1-methyl-3-(5-methoxy-(3- pyridyloxy)propyl))methylamine, for which X is C-OCH 3 , X' is N, B' is O, n is 1 , m is 2, A, A', A", E, E', E" and Z' are each H, and E'" and Z" are each methyl.
  • One representative compound is (4-(3-pyridyloxy)butyl))methylamine, for which X is CH, X' is N, B' is O, n is 0, m is 4, A, A', A", E, E', and Z' are each H, and Z" is methyl.
  • One representative example is (3-phenoxypropyl)methylamine, for which X and X' are each CH, B' is O, n is 0, m is 3, A, A', A", E, E' and Z' are each H, and Z" is methyl.
  • One representative example is (3-(3- aminophenoxy)propyl)methylamine, for which X is CH, X 1 is C-NH 2 , B' is O, n is 0, m is 3, A, A', A", E, E' and Z' are each H, and Z" is methyl.
  • One representative example is (3-(4-methoxyphenoxy)propyl)methylamine, for which X and X' are each CH, B' is O, n is 0, m is 3, A, A', E, E' and Z' are each H, A" is OCH 3 , and Z" is methyl.
  • Exemplary other compounds that can be made in accordance with the present invention include (2-(5-bromo(3-pyridylthio))ethyl)methylamine, (2-(5- bromo(3-pyridylthio))isopropyl)methylamine, (2-(5-bromo(3- pyridylthio))propyl)methylamine and (3-(5-bromo(3- pyridylthio))propyl)methylamine, dimethyl(2-(3-pyridyloxy)ethylamine, dimethyl(4-(3-pyridyloxy)butyl)amine, 2-(3-pyridyloxy)ethylamine, 4-(3- pyridyloxy)butylamine, methyl (3-(5-methoxy-3-pyridyloxy)propyl)amine, ethyl(3- (3-pyridyloxy)propyl)amine, methyl
  • Certain phenoxyalkylamine compounds of the present invention can be prepared by the alkylation of phenol with a 1 ,3-dihalopropane, such as 1 ,3-dichloropropane, 1 ,3-dibromopropane, 1 ,3-diiodopropane, or 1 -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-1-phen ⁇ xypropane can be converted to a phenoxyalkylamine, such as methyl(3-phenoxypropyl)amine, by treatment with methylamine in a solvent, such as tetrahydrofuran or aqueous methanol.
  • a solvent such as tetrahydrofuran or aqueous methanol.
  • one representative compound, (3-(3- aminophenoxy)propyl)methylamine can be prepared by the alkylation of an N- phthalamido-protected phenol, 2-(3-hydroxyphenyl)isoindoline-1 ,3-dione (prepared by treatment of 3-aminophenol with phthalic anhydride) with 1 -chloro- 3-iodopropane.
  • the resulting intermediate, 2-(3-(3-chloropropoxy)- phenyl)isoindoline-1 ,3-dione can be converted to (3-(3-aminophenoxy)- propyDmethylamine by treatment with methanolic methylamine.
  • Certain pyridyloxyalkylamine compounds can be prepared by the alkylation of 3-hydroxypyridine with a 1 ,3-dihalopropane, such as 1 ,3-dichloropropane, 1 ,3-dibromopropane, 1 ,3-diodopropane or 1- 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-1-(3-pyridyloxy)propane can be converted to a pyridyloxyalkylamine, such as (3-(3- pyridyloxy)propyl)methylamine, by treatment with methylamine in a solvent, such as tetrahydrofuran or aqueous methanol.
  • a solvent such as tetrahydrofuran or aqueous methanol.
  • One representative compound, (3-(3-pyridyloxy)propyl)methylamine is prepared by the reaction of 3- hydroxypyridine with 1.2 molar equivalents of 1-chloro-3-iodopropane and 1.6 molar equivalents of sodium hydride in dry N,N-dimethylformamide at ambient temperature.
  • Certain pyridyloxyalkylamine compounds such as (4-(3-pyridyloxy)- butyOmethylamine, can be prepared by alkylating 3-hydoxypyridine with a 1 ,4- dihalobutane, such as 1,4-diiodobutane, 1 ,4-dibromobutane, 1 ,4-dichlorobutane or 1 -chloro-4-iodobutane, which are commercially available from Aldrich Chemical Company, in the presence of a base (e.g., sodium hydride) in N,N- dimethylformamide.
  • a base e.g., sodium hydride
  • the resulting 4-halo-1 -(3-pyridyloxy)butane can be converted to a pyridyloxyalkylamine, such as (4-(3- pyridyloxy)butyl)methylamine, by treatment with methylamine in a solvent, such as tetrahydrofuran or aqueous methanol.
  • a solvent such as tetrahydrofuran or aqueous methanol.
  • 5-substituted-3-pyridyl analogs of (3-(3- pyridyloxy)propyl)methylamine of the present invention can be synthesized is analogous to that described for (3-(3-pyridyloxy)propyl)methylamine, with the exception that 5-substituted-3-hydroxypyridines are employed rather than 3- hydroxypyridine.
  • 5-bromo-3- hydroxypyridine can be converted to the intermediate, 3-chloro-1 -(5-bromo-3- pyridyloxy)propane, which is converted to 3-(5-bromo(3-pyridyloxy))- propyDmethylamine.
  • 5-Bromo-3-hydroxypyridine can be prepared form 2- furfurylamine using the procedure described in U.S. Patent No. 4,192,946 to
  • 5-ethoxy-3-hydroxypyridine can be converted to 3-(5-ethoxy(3-pyridyloxy))propyl)methylamine.
  • 5-amino- 3-hydroxypyridine prepared according to the procedures set forth in Tamura et al., Heterocycles 15(2): 871 (1981 ), can be converted to 3-(5-amino(3- pyridyloxy))propyl)methylamine.
  • 3-hydroxy-5- trifluoromethylpyridine and 2-fluoro-5-hydroxy-3-methylpyridine each prepared using methods set forth in PCT WO 96/40682, can be converted to 3-(5- trifluoromethyl(3-pyridyloxy))propyl)methylamine and 3-(6-fluoro-5-methyl(3- pyridyloxy))propyl)methylamine, respectively.
  • a number of 5-substituted analogs such as (3-(5-substituted(3- pyridyloxy))propyl)methylamine, can be synthesized from 5-substituted 3- hydroxypyridines, which can be prepared from 5-amino-3-hydroxypyridine via a diazonium salt intermediate.
  • 5-amino-3-hydroxypyridine can be converted to 5-fluoro-3-hydroxypyridine, 5-chloro-3-hydroxypyridine, 5-bromo- 3-hydroxypyridine, 5-iodo-3-hydroxypyridine or 5-cyano-3-hydroxypyridine, using the general techniques set forth in Zwart et al., Recueil Trav. Chim. Pays- Bas 74: 1062 (1955).
  • 5-hydroxy-substituted analogs can be prepared from the reaction of the corresponding 5-diazonium salt intermediate with water.
  • the 5-fluoro-substituted analogs can be prepared from the reaction of the 5-diazonium salt intermediate with fluoroboric acid.
  • the 5-chloro- substituted analogs can be prepared from the reaction of 5-amino-3- hydroxypyridine with sodium nitrite and hydrochloric acid in the presence of copper chloride.
  • the 5-cyano-substituted analogs can be prepared from the reaction of the corresponding diazonium salt intermediate with potassium copper cyanide.
  • the 5-amino-substituted analogs can be converted to the corresponding 5-nitro analogs by reaction with fuming sulfuric acid and peroxide according to the general techniques described in Morisawa, /. Med. Chem. 20: 129 (1977), for converting an amino pyridine to a nitropyridine.
  • Certain pyridyloxyalklylamines that possess a branched side chain can be prepared by alkylating 3-hydroxypyridine with a protected 3-hydroxy-1 -halobutane, such as 3-[(tert- butyl)dimethylsilyloxy]-1 -bromobutane (prepared according to the procedures set forth in Gerlach et al., Helv. Chim. Acta. 60(8): 2860 (1977)), thereby producing a (tert-butyl)dimethylsilyl protected 4-(3-pyridyloxy)butan-2-ol.
  • a protected 3-hydroxy-1 -halobutane such as 3-[(tert- butyl)dimethylsilyloxy]-1 -bromobutane
  • the (tert- butyDdimethylsilyl group can be removed by treatment with ammonium fluoride or aqueous acetic acid to give 4-(3-pyridyloxy)butan-2-ol.
  • pyridyloxyalkylamines possessing a branched side chain such as (1-methyl-3-(3-pyridyloxy)propyl)methylamine
  • pyridyloxyalkylamines possessing a branched side chain such as (1-methyl-3-(3-pyridyloxy)propyl)methylamine
  • a protected 1 -iodo-3-butanone namely 2- methyl-2-(2-iodoethyl)-1 ,3-dioxolane
  • the resulting ketal, 3-(2-(1-methyl-2,5-dioxolanyl)ethoxy)pyridine can be protected by treatment with aqueous acetic acid or p-toluenesulfonic acid in methanol to yield 4-(3-pyridyloxy)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 (1-methyl-3-(3- pyridyloxy)propyl)methylamine.
  • the intermediate, 4-(3- pyridyloxy)butan-2-one can be reduced with sodium borohydride to yield an alcohol, 4-(3-pyridyloxy)butan-2-ol.
  • Mesylation or tosylation of that alcohol, followed by mesylation or tosylation displacement using methylamine provides the branched chain pyridyloxyalkylamine, (1-methyl-3-(3- pyridyloxy)propyl)methylamine.
  • Chiral starting materials are available for the synthesis of the pure enantiomers of the branched chain pyridyloxyalkylamines, such a (1 -methyl-3-(3- pyridyloxy)proyl)methylamine.
  • 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., /.
  • the resulting chiral alcohol can be elaborated to the chiral pyridyloxyalkylamine, (1 S-3-(3-pyridyloxy)propyl)methylamine using a two-step sequence involving tosylation and methylamine displacement of the intermediate tosylate.
  • (S)-( + )-3-hydroxybutyrate can be converted to (S)-( + )-3-tetrahydropyranyloxybutyl bromide using the procedures set forth in Sakai et al., Agric. Biol. Chem. 50(6): 1621 (1986).
  • This protected bromo alcohol can be converted to the corresponding chiral pyridyloxyalkylamine, methyl(1 R-3-(3-pyridyloxy)propyl)amine, using a sequence involving alkylation of 3-hydroxypyridine, removal of the tetrahydropyranyl group, tosylation, and methylamine displacement of the intermediate tosylate.
  • 3,5-dibromopyridine (commercially available from Aldrich Chemical Company and Lancaster Synthesis Inc.) can be converted to the synthetic intermediate, 5-(3,4- dimethoxybenzyloxy)-3-bromopyridine by heating at 100°C with veratryl alcohol (3,4-dimethoxybenzyl alcohol) in the presence of sodium and copper powder.
  • the resulting 5-(3,4-dimethoxybenzyloxy)-3-bromopyridine can be heated at 180°C with concentrated aqueous ammonia in the presence of copper(ll) sulfate or copper (I) bromide to produce the aminopyridine compound, 5-(3,4- dimethoxybenzyloxy)-3-aminopyridine.
  • the latter compound can be diazotized and the diazonium salt hydrolyzed by treatment with sodium nitrite and aqueous sulfuric acid to give the hydroxypyridine, 5-(3,4-dimethoxybenzyloxy)-3- hydroxypyridine.
  • This 5-substituted-3-hydroxypyridine can be alkylated with 1- chloro-3-iodopyridine in the presence of sodium hydride in N,N- dimethylformamide to yield 3-chloro-1-(5-(3,4-dimethoxybenzyloxy)-3- pyridyloxy)propane.
  • Treatment of the latter compound with an excess of methylamine in methanol will afford methyl(3-(5-(3,4-dimethoxybenzyloxy)(3- pyridyloxy))propyl)methylamine.
  • fused polycyclic haloaromatics can be used as starting materials to prepare compounds of the present invention which possess fused rings.
  • 3-bromoquinoline (commercially available from Aldrich Chemical Company) can be converted to 3-aminoquinoline by heating at aboutl 80°C with aqueous ammonia in the presence of copper(ll) sulfate or copper(l) bromide.
  • the resulting 3-aminoquinoline (commercially available from Aldrich Chemical Company) can be diazotized and subsequently hydrolyzed by treatment with sodium nitrite and aqueous sulfuric acid to produce 3-hydroxyquinoline according to the methodology of C. Naumann and H. Langhals, Synthesis (4): 279-281 (1990).
  • 3-Hydroxyquinoline can be alkylated with 1 -chloro-3-iodopyridine in the presence of sodium hydride and N,N-dimethylformamide to give 3-chloro-1-(3-quinolyloxy)propane. Treatment of the latter compound with aqueous methylamine will give methyl(3-(3- quinolyloxy)propyl)amine.
  • Compounds of the present invention possessing a thioether moiety can be prepared from an appropriately substituted pyridine such as 3,5-dibromopyridine (commercially available from Aldrich Chemical Company and Lancaster Synthesis Inc.).
  • 3,5-dibromopyridine can be treated with 3- mercapto-1 -propanol in the presence of sodium hydroxide and N,N- dimethylformamide to give 3-(5-bromo-3-pyridylthio)propan-1-ol.
  • 3-((3S)- N-(tert-butoxycarbonyl)-3-pyrrolidinyloxy)pyridine can then be treated with a strong acid such as trifluoroacetic acid to remove the tert-butoxycarbonyl protecting group to produce 3-((3S)-3-pyrrolidinyloxy)pyridine.
  • the latter compound can be N-methylated to afford 3-((3S)-(1 -methyl-3- pyrrolidinyloxy)pyridine.
  • Methylation methods employing aqueous formaldehyde and sodium cyanoborohydride as described by M. A. Abreo et al., /. 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., /. Chem. Soc. Perkin Trans 1 (Issue 13): 1421 -1424 (1993).
  • 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 reoccurrence 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.
  • the present invention also relates to prodrug derivatives of the compounds of the present invention.
  • the compounds normally are not optically active. However, certain compounds can possess substituent groups of a character so that those compounds possess optical activity. 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; and salts with basic amino acid such as lysine salt and arginine salt.
  • the salts may be in some
  • 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, anti-pyretics, time release binders, anaesthetics, steroids 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, for example, 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.
  • the appropriate dose of the compound is that amount effective to prevent occurrence of the symptoms of the disorder or to treat some symptoms of the disorder from which the patient suffers.
  • effective amount By “effective amount”, “therapeutic amount” or “effective dose” is meant that amount sufficient to elicit the desired pharmacological or therapeutic effects, 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 activatie 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 1 ug/kg of patient weight.
  • the compounds of the present invention are administered in an amount from 10 ng to less than 1 ug/kg of patient weight, frequently between about O.I ug to less than 1 ug/kg of patient weight, and preferably between about 0.1 ug to about 0.5 ug/kg of patient weight.
  • Compounds of the present invention can be administered in an amount of 0.3 to 0.5 ug/kg of patient weight.
  • the effective dose is less than 50 ug/kg of patient weight; and often such compounds are administered in an amount from 0.5 ug to less than 50 ug/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 hrJ 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 hrJ 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., /. 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 1 uM, often are less than about 100 nM, and frequently are less than about 50 nM. Though not preferred, certain compounds possess receptor binding constants of less than 10 uM, and even less than 100 uM. 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 neurotransmitters.
  • 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 (SH-)-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 muscle- 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.
  • This selectivity of certain compounds of the present invention against those ganglia-type receptors responsible for cardiovascular side effects is demonstrated by a lack of the ability of those compounds to activate nicotinic function of adrenal chromaffin tissue at concentrations greater 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.
  • 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.
  • administering 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 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.
  • 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 IGo 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.
  • Rat brain synaptosomes were prepared as follows: Female Sprague Dawley rats (100-200 g) were killed by decapitation after anesthesia with 70% C0 2 . 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 KH 2 P0 4 , 2.4 mM KCl, 3.2 mM CaCb, 1.2 mM
  • 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 (Emax) was determined as a percentage of the maximal activation induced by (S)-(-)-nicotine.
  • Reported Ema values represent the amount released relative to (SH-)-nicotine on a percentage basis.
  • Low Emax 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 compounds begin to cause muscle effects only when employed in amounts of many times those required to activate dopamine release.
  • 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 (Emax) was determined as a percentage of the maximal activation induced by (SH-)-nicotine.
  • Reported Emax values represent the amount released relative to (SH-)-nicotine on a percentage basis.
  • Low Emax 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.
  • the combined CH2CI2 extracts were washed with saturated NaCl solution (50 mL), dried (Na 2 S0 4 ), filtered, concentrated (rotary evaporator, using toluene (3 x 20 mL) to azeotropically remove pyridine) and further dried under high vacuum to afford a dark-red oil (2.65 g).
  • the oil was dissolved in methanol (20 mL) and transferred to a heavy-walled glass pressure- tube apparatus. A 40 wt% aqueous solution of methylamine (80 mL) was added. The tube was sealed and the mixture was stirred and heated at 120°C for 2.5 h. The resulting brown solution was allowed to cool to ambient temperature and was further stirred for 16 h.
  • the crude product was purified by column chromatography on silica gel (80 g), eluting with EtOAc-hexane (3: 1 , v/v) to collect 1 -(5-bromo-3- pyridylthio)propan-2-ol (Rf 0.38) (0.05 g). Further elution with MeOH-E N (97:3, v/v) afforded a brown oil (Rf 0.58). The oil was dissolved in CHC .
  • the combined CH 2 CI 2 extracts were washed with saturated NaCl solution (100 mL), dried (Na S0 4 ), filtered and concentrated (rotary evaporator) to a dark red oil (10.22 g).
  • the oil was transferred to a heavy-walled glass pressure-tube apparatus with methanol (25 mL), and a 40 wt% aqueous solution of methylamine (100 mL) was added.
  • the tube was sealed and the mixture was stirred and heated at 120°C (oil bath temperature) for 2 h.
  • the resulting solution was allowed to cool to ambient temperature and was further stirred for 16 h.
  • the solution was concentrated on a rotary evaporator.
  • the resulting oil was basified with 1 M NaOH solution (30 mL) and extracted with CHCb (5 x 30 mL). The combined CHCb extracts were washed with saturated NaCl solution (50 mL), dried (Na 2 S0 ), filtered and concentrated to a brown oil.
  • the crude product was purified by column chromatography on silica gel (190 g), eluting with EtOAc-hexane (3:1 , v/v) to collect 3-(5-bromo-3-pyridylthio)propan-1-ol (Rf 0.40) (0.46 g).
  • Example 8 The solvent was removed by rotary evaporation, and the resulting solids were vacuum dried at 40°C for 24 h. The resulting solids were slurried in 2-propanol, and subsequently diluted with anhydrous ether. The solids were filtered, washed with ether, and vacuum dried at 40°C for 24 h to give 0.598 g (87.1 %) of a fluffy, off-white powder, mp 151- 156°C. The compound exhibits a Ki of 1600 nM. The compound exhibits neurotransmitter release of 30 percent.
  • Example 8 The solvent was removed by rotary evaporation, and the resulting solids were vacuum dried at 40°C for 24 h. The resulting solids were slurried in 2-propanol, and subsequently diluted with anhydrous ether. The solids were filtered, washed with ether, and vacuum dried at 40°C for 24 h to give 0.598 g (87.1 %) of a fluffy, off-white powder,
  • the 2-chloro-1 -(3-pyridyloxy)ethane (2.1 7 g, 13.8 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% HCI solution and impurities were extracted with chloroform (2 x 50 mL).
  • the resulting solids were filtered, washed with cold ethanol (4 mL), and vacuum dried at 40°C to give 0.307 g (77.9%) of a white to off-white, crystalline powder, mp 148.5- 151.5°C (d).
  • the compound exhibits a Ki of 65 nM; the effect at muscle sites is 0 percent; and the effect at ganglia sites is 0 percent.
  • the compound exhibits neurotransmitter release of 143 percent.
  • the 2-chloro-1 -(3-pyridyloxy)ethane (2.21 g, 10.41 mmol) was dissolved in methanol (14 mL) and added to a 40 wt% aqueous solution of dimethylamine (22 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 (7 mL) and 10% NaOH solution were added to the residue (brown liquid), giving pH 12. The mixture was extracted with chloroform (4 x 20 mL).
  • the combined chloroform extracts were dried (Na 2 S0 4 ), filtered, and concentrated by rotary evaporation to a residue that was dried briefly under high vacuum to give 1 .184 g of a brown oil. Further purification was accomplished as follows: The oil was diluted with water (10 mL) and acidified to pH 6 with 10% HCI solution (6 mL). The mixture was extracted with ether (3 x 25 mL) to remove impurities. The aqueous phase was treated with saturated NaCl solution (15 mL) and basified with 10% NaOH solution to pH 12. The product was extracted with chloroform (4 x 20 mL).
  • the solids were filtered, washed with cold ethanol (5 mL), and vacuum dried at 40°C to give 344.8 mg (58.3%) of light-yellow crystals, mp 1 76-1 78°C.
  • the compound exhibits a Ki of 65 nM; the effect at muscle sites is 0 percent; and the effect at ganglia sites is 0 percent.
  • the compound exhibits a Ki of 12 nM; the effect at muscle sites is 0 percent; and the effect at ganglia sites is 0 percent.
  • the compound exhibits neurotransmitter release of 0 percent.
  • the 3-chloro-1-(3-pyridyloxy)propane (2.00 g, 1 1 .65 mmol) was dissolved in methanol (25 mL) and added to a 40 wt% aqueous solution of dimethylamine (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 of the solution was adjusted to 6, and the mixture was extracted with ether (3 x 25 mL) to remove impurities.
  • the warm solution was filtered through a glass wool plug, washing the filter plug with a warm solution of ethanol-water (4:1 , v/v).
  • the filtrate was diluted with ethanol (80 mL).
  • the mixture was allowed to cool to ambient temperature and was further cooled at 5°C for 16 h. No solids precipitated. Consequently, the solution was concentrated to a crystalline solid.
  • the solid was slurried in ether, filtered, washed with ether, and vacuum dried at 40°C to give 1.94 g (62.7%) of brown powdery crystals, mp 137-140°C.
  • the compound exhibits a Ki of 126 nM; the effect at muscle sites is 8 percent; and the effect at ganglia sites is 5 percent.
  • the compound exhibits neurotransmitter release of 32 percent.
  • the 4-chloro-1-(3-pyridyloxy)butane (2.00 g, 10.8 mmol) was dissolved in methanol (25 mL) and added to concentrated ammonium hydroxide solution (29.7%, 14.8 M, 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 6 h. After cooling, the mixture was concentrated by rotary evaporation. Saturated NaCl solution (10 mL) was added to the residue, and the solution (pH 6) was extracted with ether (3 x 25 mL) to remove impurities.
  • the product was slurried in 2-propanol, and the 2-propanol was decanted.
  • the product was vacuum dried at 40°C to give 1 .28 g (62.7%) of fine, white powder, mp 1 77-180°C.
  • the compound exhibits a Ki of 232 nM; the effect at muscle sites is 0 percent; and the effect at ganglia sites is 1 1 percent.
  • the compound exhibits neurotransmitter release of 100 percent.
  • the solids were filtered, washed with cold ethanol and vacuum dried at 40°C to give 1 .69 g (72.8%) of a fine, white, crystalline powder, mp 1 73-1 75°C.
  • the compound exhibits a Ki of 5523 nM.
  • the compound exhibits neurotransmitter release of 56 percent.
  • 3-(5-Chloro-3-pyridyloxy)propylamine The 3-chloro-5-(3-chloropropoxy)pyridine (5.74 g, 28.0 mmol) was dissolved in methanol (25 mL) and added to concentrated ammonium hydroxide solution (29.7%, 14.8 M, 55 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 6 h. After cooling, the mixture was concentrated by rotary evaporation. Saturated NaCl solution (10 mL) was added to the residue, and the solution (pH 6) was extracted with ether (3 x 25 mL) to remove impurities.
  • the 3-chloro-5-(3-chloropropoxy)pyridine (5.74 g, 28.0 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 of the solution was adjusted to 6, and impurities were extracted with ether (3 x 15 mL).
  • the solids were filtered, washed and vacuum dried at 40°C to give 1 .163 g (76.3%) of off-white, powdery crystals, mp 1 73-1 74°C.
  • the compound exhibits a Ki of 1 1 nM; the effect at muscle sites is 16 percent; and the effect at ganglia sites is 7 percent.
  • the compound exhibits neurotransmitter release of 100 percent.
  • the combined ether extracts were dried (MgS0 ), filtered and concentrated by rotary evaporation to give 0.54 g of a brown oil.
  • the product was purified by column chromatography on silica gel (18 g) eluting with CHCb- CH 3 OH (1 :1 , v/v) to remove impurities, followed by CHCb-CH 3 OH-Et 3 N (50:50:2, v/v/v) to collect the product. Selected fractions containing the product were combined and concentrated by rotary evaporation.
  • the precipitate was filtered, washed with ethanol (10 mL), and vacuum dried at 40°C for 24 h to give 141 .2 mg (80.77o) of a white, crystalline solid, mp 140-141 °C.
  • the compound exhibits a Ki of 15 nM; the effect at muscle sites is 10 percent; and the effect at ganglia sites is 5 percent.
  • the compound exhibits neurotransmitter release of 54 percent.
  • Potassium metal (6.59 g, 168.84 mmol) was dissolved in dry 2-propanol (60.0 mL) under nitrogen.
  • the resulting potassium isopropoxide was heated with 3,5-dibromopyridine (20.00 g, 84.42 mmol) and copper powder (1 g, 57o by weight of 3,5-dibromopyridine) at 140°C (oil bath temperature) in a sealed glass tube for 14 h.
  • the reaction mixture was cooled to ambient temperature and extracted with diethyl ether (4 x 200 mL). The combined ether extracts were dried over sodium sulfate, filtered, and concentrated by rotary evaporation.
  • the crude product obtained was purified by column chromatography over aluminum oxide, eluting with ethyl acetate-hexane (1 :9, v/v). Selected fractions were combined and concentrated by rotary evaporation, producing a pale-yellow oil (12.99 g, 71.2%).
  • the combined ether extracts were dried (MgS0 4 ), filtered and concentrated by rotary evaporation to give 1 .98 g of a brown oil.
  • the product was purified by column chromatography on silica gel (60 g) eluting with hexane to remove impurities, followed by CHCb-CH 3 OH-Et 3 N (50:50:2, v/v/v) to collect the product. Selected fractions containing the product were combined and concentrated by rotary evaporation.
  • the resulting brown oil was dissolved in CHCb (25 mL), dried (MgS0 4 ), filtered, and concentrated by rotary evaporation to give 0.64 g (71 .67o) of a brown oil.
  • the precipitate was filtered, washed with ethanol (10 mL), and vacuum dried at 40°C for 24 h to give 251.1 mg (53.27o) of a white, crystalline solid, mp 1 18-120°C.
  • the compound exhibits a Ki of 21 nM; the effect at muscle sites is 22 percent; and the effect at ganglia sites is 0 percent.
  • the compound exhibits neurotransmitter release of 36 percent.
  • the tube was sealed and the dark blue suspension was stirred and heated at ⁇ 180°C (oil bath temperature) for 24 h.
  • the mixture was allowed to cool to ambient temperature. After further cooling in an ice-water bath, the mixture was concentrated on a rotary evaporator to a small volume (-20 mL) of a dark-blue solution.
  • the solution was diluted with water (40 mL) and saturated K 2 C0 solution (40 mL) and extracted with CHCb (4 x 40 mL).
  • the combined, turbid- brown CHCb extracts were washed with saturated NaCl solution (2 x 100 ml), dried (Na 2 S0 ), filtered and concentrated (rotary evaporator).
  • the 5-(3-chloropropoxy)-3-(phenylmethoxy)pyridine (1.52 g, 5.49 mmol) was dissolved in methanol (25 mL) and added to a 40 wt7o 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 of the solution was adjusted to 6, and impurities were extracted with ether (3 x 1 5 mL).
  • the solution was concentrated by rotary evaporation and briefly dried under high vacuum.
  • the resulting brown solids were dissolved in a mixture of hot 2-propanol (-15 mL) and water (0.8 mL); the dark-brown solution was allowed to cool to ambient temperature. After 30 min of precipitation, the batch was diluted with 2-propanol (30 mL) and stored at 5°C for 16 h. The resulting solids were filtered, washed with cold 2-propanol (3 x 5 mL) and vacuum dried at 45°C to give 0.967 g (65.27o) of a beige powder, mp 137- 140°C.
  • the compound exhibits a Ki of 2 nM; the effect at muscle sites is 1 percent; and the effect at ganglia sites is 3 percent.
  • the compound exhibits neurotransmitter release of 38 percent.
  • the resulting solids were filtered, washed with cold ethanol, and vacuum dried at 40°C to give 1 .596 g (82.37o) of a white, fluffy crystalline powder, mp 152- 155°C.
  • the compound exhibits a Ki of 12 nM; and the effect at muscle sites is 0 percent.
  • the compound exhibits neurotransmitter release of 77 percent.
  • the aqueous layer was basified to pH 10 with 107o NaOH solution, and the mixture was extracted with chloroform (4 x 25 mL).
  • the combined chloroform extracts were dried (Na 2 S0 4 ), filtered, and concentrated by rotary evaporation to a residue that was dried briefly under high vacuum to give 0.531 g (58.67o) of a dark-brown oil.
  • the compound exhibits a Ki of 8500 nM.
  • the compound exhibits neurotransmitter release of 16 percent.
  • the tube was sealed and the mixture was stirred and heated at 120°C (oil bath temperature) for 3 h. After cooling, the mixture was concentrated by rotary evaporation, and saturated NaCl solution (25 mL) was added to the residue.
  • the mixture was acidified to pH 1 with 107o HCI solution and extracted with CHCb (2 x 35 mL) to remove impurities.
  • the aqueous phase was basified to pH 10 with 107o NaOH solution, and the mixture was extracted with chloroform (4 x 50 mL).
  • the combined chloroform extracts were dried (MgS0 4 ), filtered, and concentrated by rotary evaporation to a residue that was dried briefly under high vacuum to give a brown oil.
  • the residue was dissolved in CHCL and the CHCL 3 solution was dried (MgS0 ), filtered, and concentrated by rotary evaporation to a residue that was dried briefly under high vacuum to give 20 mg (2.27o) of a light-brown oil.
  • the compound exhibits a Ki of 3000 nM.
  • the compound exhibits neurotransmitter release of 29 percent.
  • the aqueous phase was basified to pH 6 with 107o NaOH solution and extracted (4 x 25 mL) to remove other impurities.
  • the aqueous phase was basified to pH 10 with 107o NaOH solution and extracted with CHCb (4 x 50 mL).
  • the combined CHCb extracts were dried (Na 2 S0 4 ), filtered, concentrated (rotary evaporator) and briefly dried under high vacuum to give 0.250 g of a brown oil.
  • the oil was purified by column chromatography on silica gel (20 g) eluting with CHCb-CH 3 OH (100:2) to remove impurities, followed by CHCb-CH 3 OH-Et 3 N (50:50:2) to remove the product. Selected fractions were combined to give 220 mg (25.87o) of a brown semi-solid. Cyclopropyl(3-(3-pyridyloxy)propyl)amine Hemigalactarate
  • the syrup was slurried in a mixture of 2-propanol-diethyl ether, producing a somewhat powdery solid.
  • the solvents were evaporated on a rotary evaporator, and the resulting solids were slurried in a mixture of 2-propanol-diethyl ether.
  • the mixture was stored at 5°C for 24 h.
  • the solvent was decanted; the tan solids were washed with ether (3 x 5 mL), decanting the wash each time.
  • the tan solids were dried under a stream of nitrogen and under high vacuum to give 0.246 g (66.57o) of a light-beige powder, mp 124-130°C.
  • the compound exhibits a Ki of 165 nM; the effect at muscle sites is 9 percent; and the effect at ganglia sites is 10 percent.
  • the compound exhibits neurotransmitter release of 51 percent.
  • the precipitate was filtered, washed with ethanol (10 mL), and vacuum dried at 40°C for 24 h to give 61 7 mg (83.57o) of white, fluffy, crystals, mp 186-187°C.
  • the compound exhibits a Ki of 392 nM; the effect at muscle sites is 10 percent; and the effect at ganglia sites is 9 percent.
  • the compound exhibits neurotransmitter release of 67 percent.
  • the 3-(3-chloropropoxy)phenylamine (1 .98 g, 1 1 .6 mmol) was dissolved in methanol (25 mL) and added to concentrated ammonium hydroxide solution (29.7%, 14.8 M, 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 6 h. After cooling, the mixture was concentrated by rotary evaporation. Saturated NaCl solution (10 mL) was added to the residue, and the solution (pH 6) was extracted with ether (3 x 25 mL) to remove impurities.
  • the solids were slurried in hot 2-propanol and cooled to ambient temperature. The product was filtered, washed with 2-propanol and vacuum dried at 40°C to give 1 .462 g (65.47o) of a beige, crystalline powder, mp 182- 185°C. The compound exhibits a Ki of 442 nM. The compound exhibits neurotransmitter release of 14 percent.
  • the 3-(3-chloropropoxy)phenylamine was dissolved in methanol (25 mL) and added to a 40 wt7o 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 of the solution was adjusted to 6, and impurities were extracted with ether (4 x 30 mL). The aqueous layer was basified to pH 1 1 with 107o NaOH solution and extracted with chloroform (4 x 50 mL).
  • the solids were slurried in 2-propanol, and the 2-propanol was evaporated. The resulting solids were slurried in anhydrous ether. The product was filtered, washed with ether and vacuum dried at 40°C to give 3.928 g (89.67 ) of brown, powdery crystals, mp 160-1 70°C.
  • the compound exhibits a Ki of 64 nM; the effect at muscle sites is 1 1 percent; and the effect at ganglia sites is 5 percent.
  • the compound exhibits neurotransmitter release of 30 percent.
  • the compound exhibits neurotransmitter release of 60 percent.
  • the crude (3-(3-chloropropoxy)phenyl)dimethylamine (4.06 g, 19.01 mmol) was dissolved in methanol (30 mL) and added to a 40 wt7o aqueous solution of methylamine (75 mL) in a heavy-walled glass pressure-tube apparatus. The tube was sealed and the mixture was stirred at ambient temperature for 1 6 h, followed by heating at 87°C (oil bath temperature) for 3 h. After cooling, the solution was concentrated by rotary evaporation to a lavender- brown semi-solid. Saturated NaCl solution (35 mL) was added.
  • the mixture was acidified to pH 1 with 107o HCI solution and extracted with CHCb (5 x 30 mL) to remove impurities.
  • the dark-brown aqueous layer was basified to pH 7 with 307o NaOH solution and extracted with ether (4 x 40 mL) to remove impurities.
  • the brown aqueous layer was basified with 307o NaOH solution to pH 12 and extracted with ether (4 x 50 mL).
  • the combined ether extracts were dried
  • the warm solution was filtered through a glass wool plug, washing the filter plug with a warm solution of ethanol-water (4:1 , v/v) (10 mL).
  • the filtrate was diluted with ethanol (50 mL), producing a precipitate.
  • the mixture was allowed to cool to ambient temperature and was further cooled at 5°C for 16 h.
  • the precipitate was filtered, washed with ethanol (3 x 10 mL) and vacuum dried at 40°C for 48 h to give 2.95 g (87.97o) of a fluffy, light-gray to off-white powder, mp 159.5-162.5°C (d).
  • the compound exhibits a Ki of 10000 nM.
  • the compound exhibits neurotransmitter release of 16 percent.
  • the pH of the aqueous phase was adjusted to 7 with 107o NaOH solution, and the mixture was extracted with ether (4 x 30 mL) to remove impurities.
  • the aqueous phase was basified with 107o NaOH solution to pH 1 1 .
  • the mixture was extracted with ether (4 x 50 mL).
  • the combined ether extracts were dried (MgSQ ), filtered and concentrated by rotary evaporation to give a residue.
  • the residue was briefly dried under high vacuum producing a light- brown oil (0.1 1 g).
  • the oil was purified by column chromatography on silica gel (10 g) eluting with CHCb-CH OH (1 :1 , v/v) to remove impurities, followed by CHCIs-ChbOH-EbN (50:50:2, v/v/v) to collect the product (Rf 0.27). Selected fractions containing the product were combined and concentrated by rotary evaporation. The resulting brown oil was dissolved in CHCb, and the CHCb solution was dried (MgS0 4 ), filtered and concentrated by rotary evaporation to a residue. The residue was dried briefly under vacuum to give 0.021 g (1.77>) of a light-brown oil. The compound exhibits a Ki of 5300 nM.
  • the mixture was acidified to pH 1 with 107o HCI solution, and extracted with CHCb (4 x 25 mL) to remove impurities.
  • the pH of the aqueous phase was adjusted to 7 with 107o NaOH solution, and the mixture was extracted with ether (4 x 30 mL) to remove impurities.
  • the aqueous phase was basified with 107 NaOH solution to pH 1 1 .
  • the mixture was extracted with ether (4 x 50 mL).
  • the combined ether extracts were dried (MgS0 4 ), filtered and concentrated by rotary evaporation to give a residue.
  • the residue was briefly dried under high vacuum producing a light-brown oil (0.286 g).
  • the oil was purified by column chromatography on silica gel (20 g) eluting with CHCb-CH 3 OH (1 :1 , v/v) to remove impurities, followed by CHCb-CH 3 OH-Et 3 N (50:50:2, v/v/v) to collect the product (Rf 0.14). Selected fractions containing the product were combined and concentrated by rotary evaporation. The resulting brown oil was dissolved in CHCb and the CHCb solution was dried (MgS0 4 ), filtered and concentrated by rotary evaporation to a residue. The residue was dried under vacuum at 40°C to give 0.274 g (14.47o) of a brown oil.
  • diethyl azodicarboxylate (4.65 g, 26.70 mmol) was added to a cold (0-5°C), stirring solution of triphenylphosphine (7.00 g, 26.70 mmol) in dry tetrahydrofuran (60 mL, distilled from sodium and benzophenone). The mixture was stirred at 0-5°C for 15 min. The resulting yellow solution was treated drop-wise at 0-5°C with a solution of (3R)-N-(tert- butoxycarbonyl)-3-hydroxypyrrolidine (2.50 g, 13.35 mmol) in dry THF (20 mL) producing a thick yellow mixture.
  • Impure fractions from the latter column were combined and concentrated, and the residue was chromatographed on silica gel (50 g) to give 0.28 g of a light-yellow oil. All purified materials were combined, concentrated and dried under high vacuum to yield 1 .83 g (51 .97>) of a light- yellow oil.
  • the solution was concentrated by rotary evaporation, and the resulting residue was dissolved in CHCb (100 mL).
  • the suspension was cooled in an ice-water bath, and a solution of 1 M HCI (75 mL) was added with stirring.
  • the aqueous phase was separated.
  • the organic phase was extracted with water (3 x 75 mL).
  • the combined aqueous extracts were cooled in an ice-water bath, basified with 1 M NaOH solution (125 mL) to pH ⁇ 1 1 and extracted with CHCb (6 x 50 mL).
  • the combined organic extracts were dried (Na 2 S0 4 ), filtered, and concentrated by rotary evaporation.
  • the crude product was dissolved in CHCb (75 mL), and the CHCb solution was extracted with 1 M NaOH solution (4 x 25 mL) to remove residual 3- hydroxypyridine.
  • the CHCb phase was separated, and the combined NaOH layers were back extracted with CHCb (3 x 50 mL). All CHCb extracts were combined, dried (Na 2 S0 4 ), filtered, and concentrated by rotary evaporation.
  • the resulting oil was purified by vacuum distillation using a test-tube distillation apparatus, collecting the fraction with bp 83-93°C at 0.10-0.075 mm Hg. Further purification by a second vacuum distillation yielded 120 mg (2.47o) of a colorless oil, bp 72-75°C at 0.75 mm Hg.
  • the compound exhibits a Ki of 4897 nM.
  • the mixture was heated at 75°C (oil bath temperature) for 1 7 h. After cooling to ambient temperature, the mixture was poured into water (250 mL) and extracted with ether (3 x 75 mL). The combined ether extracts were dried (Na 2 S0 4 ), filtered and concentrated (rotary evaporator) to a light-yellow oil. The oil was vacuum distilled using a short-path distillation apparatus to afford 4.55 g (57.5%) of a light-yellow oil, bp 138-140°C at 0.35 mm Hg. (2-(5-Bromo(3-pyridylthio))ethyl)methylamine
  • the CHCb phase was separated and the aqueous phase was extracted with CHCb (3 x 10 mL). All CHCb extracts were combined and washed with saturated NaCl solution (10 mL). The CHCb extracts were concentrated (rotary evaporator) to an oil that was dried under high vacuum to yield a light beige solid (1.83 g). The solid was transferred to a heavy-walled glass pressure-tube apparatus with methanol (10 mL), and a 40 wt7o aqueous solution of methylamine (26 mL) was added. The tube was sealed and the mixture was stirred and heated at 1 1 5°C (oil bath temperature) for 45 min. The resulting solution was allowed to cool to ambient temperature and was further stirred for 16 h.
  • the solution was concentrated on a rotary evaporator.
  • the resulting oil was basified with 1 M NaOH solution (10 mL) and extracted with CHCb (4 x 10 mL).
  • the combined CHCb extracts were washed with saturated NaCl solution (10 mL), dried (Na2SQ ), filtered and concentrated to a brown oil (1 .22 g).
  • the crude product was purified by column chromatography on silica gel (50 g), eluting with EtOAc-hexane (3: 1 , v/v) to collect 2-(5-bromo-3- pyridylthio)ethan-1 -ol (Rf 0.25) (0.47 g).
  • the precipitate was filtered, washed with ethanol (4 mL) and vacuum dried at 45°C for 18 h to give 437.5 mg (87.2%) of a white, crystalline powder, mp 161 .5-1 66°C (d).
  • the compound exhibits a Ki of 3400 nM.

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
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  • Medicinal Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Psychiatry (AREA)
  • Psychology (AREA)
  • Hospice & Palliative Care (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyridine Compounds (AREA)
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Abstract

Des patients susceptibles de souffrir ou souffrant de pathologies ou de troubles, tel que les troubles du système nerveux central, sont traités par l'administration d'aryloxyalkylamines et d'arylthioalkylamines, comprenant des pyridyloxylalkylamines, des phénoxyalkylamines, des pyridylthiolalkylamines et des phénylthiolalkylamines.
PCT/US2000/011256 1999-05-24 2000-04-27 Compositions pharmaceutiques et methodes d'utilisation WO2000071520A2 (fr)

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MXPA01012202A MXPA01012202A (es) 1999-05-24 2000-04-27 Composiciones farmaceuticas y metodos de uso.
EP00928437A EP1185513A2 (fr) 1999-05-24 2000-04-27 Compositions pharmaceutiques et methodes d'utilisation
CA002373789A CA2373789A1 (fr) 1999-05-24 2000-04-27 Compositions pharmaceutiques et methodes d'utilisation
KR1020017015045A KR20020010670A (ko) 1999-05-24 2000-04-27 니코틴 콜린성 수용체를 활성화시킬 수 있는 아릴치환된알킬아민
BR0011534-7A BR0011534A (pt) 1999-05-24 2000-04-27 Alquilaminas aril substituìdas capazes de ativação de receptores colinérgicos nicotìnicos
JP2000619777A JP2003500393A (ja) 1999-05-24 2000-04-27 薬学的組成物およびその使用
AU46678/00A AU4667800A (en) 1999-05-24 2000-04-27 Pharmaceutical compositions and methods for use

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US09/317,327 US20010031771A1 (en) 1999-05-24 1999-05-24 Pharmaceutical compositions and methods for use
US32714999A 1999-06-07 1999-06-07
US09/327,149 1999-06-07

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Cited By (9)

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WO2001056991A1 (fr) * 2000-02-02 2001-08-09 Abbott Laboratories Composes pyridine substitues utiles dans la regulation de la transmission synaptique chimique
US6656958B2 (en) 2000-02-02 2003-12-02 Abbott Laboratories Substituted pyridine compounds useful for controlling chemical synaptic transmission
WO2006015279A1 (fr) * 2004-07-28 2006-02-09 Neurogen Corporation Composés de diamine hétérocyclique comme liants du récepteur d'hormone concentrant de la mélamine, utile pour le traitement de l'obésité, du diabète et des troubles sexuels et de l'alimentation
US7067261B2 (en) 2001-12-14 2006-06-27 Targacept, Inc. Methods and compositions for treatment of central nervous system disorders
US7160876B2 (en) 2003-12-22 2007-01-09 Abbott Laboratories Fused bicycloheterocycle substituted quinuclidine derivatives
WO2009067579A1 (fr) * 2007-11-21 2009-05-28 Abbott Laboratories Dérivés d'alcane azabicyclique à substitution biaryle en tant que modulateurs de l'activité du récepteur nicotinique de l'acétylcholine
US7655657B2 (en) 2003-12-22 2010-02-02 Abbott Laboratories Fused bicycloheterocycle substituted quinuclidine derivatives
US7897766B2 (en) 2005-09-23 2011-03-01 Abbott Laboratories Amino-aza-adamantane derivatives and methods of use
US8987453B2 (en) 2006-11-06 2015-03-24 Abbvie Inc. Azaadamantane derivatives and methods of use

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DE19956786A1 (de) * 1999-11-25 2001-05-31 Basf Ag Verfahren zur Herstellung optisch aktiver Amine
KR100743617B1 (ko) * 2005-08-25 2007-07-27 주식회사 알에스텍 고광학순도를 갖는 키랄 3-히드록시 피롤리딘 및 그유도체를 제조하는 방법
BR122014023207A2 (pt) 2010-09-23 2019-05-28 Abbvie Inc. Compostos derivados de aza-adamantano, seus usos e processos para a preparação destes compostos

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JPS63264466A (ja) * 1986-12-05 1988-11-01 Tooa Eiyoo Kk 新規フエノキシアルキルアミン誘導体及びその製造法
US5731314A (en) * 1995-01-06 1998-03-24 Bencherif; Merouane Pharamceutical compositions for prevention and treatment of tourette's syndrome
US6166048A (en) * 1999-04-20 2000-12-26 Targacept, Inc. Pharmaceutical compositions for inhibition of cytokine production and secretion
JP2002510619A (ja) * 1998-04-02 2002-04-09 アール・ジェイ・レイノルズ・タバコ・カンパニー 薬剤組成物及びその使用法
CA2376061A1 (fr) * 1999-06-07 2000-12-14 Targacept, Inc. Compositions pharmaceutiques et methodes d'utilisation

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6656958B2 (en) 2000-02-02 2003-12-02 Abbott Laboratories Substituted pyridine compounds useful for controlling chemical synaptic transmission
WO2001056991A1 (fr) * 2000-02-02 2001-08-09 Abbott Laboratories Composes pyridine substitues utiles dans la regulation de la transmission synaptique chimique
US7067261B2 (en) 2001-12-14 2006-06-27 Targacept, Inc. Methods and compositions for treatment of central nervous system disorders
US7655657B2 (en) 2003-12-22 2010-02-02 Abbott Laboratories Fused bicycloheterocycle substituted quinuclidine derivatives
US7160876B2 (en) 2003-12-22 2007-01-09 Abbott Laboratories Fused bicycloheterocycle substituted quinuclidine derivatives
US7674794B2 (en) 2003-12-22 2010-03-09 Abbott Laboratories Fused bicycloheterocycle substituted quinuclidine derivatives
WO2006015279A1 (fr) * 2004-07-28 2006-02-09 Neurogen Corporation Composés de diamine hétérocyclique comme liants du récepteur d'hormone concentrant de la mélamine, utile pour le traitement de l'obésité, du diabète et des troubles sexuels et de l'alimentation
US7897766B2 (en) 2005-09-23 2011-03-01 Abbott Laboratories Amino-aza-adamantane derivatives and methods of use
US8586746B2 (en) 2005-09-23 2013-11-19 Abbvie Inc. Amino-aza-adamantane derivatives and methods of use
US8987453B2 (en) 2006-11-06 2015-03-24 Abbvie Inc. Azaadamantane derivatives and methods of use
WO2009067579A1 (fr) * 2007-11-21 2009-05-28 Abbott Laboratories Dérivés d'alcane azabicyclique à substitution biaryle en tant que modulateurs de l'activité du récepteur nicotinique de l'acétylcholine
US7902222B2 (en) 2007-11-21 2011-03-08 Abbott Laboratories Biaryl substituted azabicyclic alkane derivatives
EP2280010A3 (fr) * 2007-11-21 2011-05-04 Abbott Laboratories Dérivés d'alcane azabicyclique à substitution biaryle en tant que modulateurs de l'activité du récepteur nicotinique de l'acétylcholine dérivés d'alcanes azabicycliques
US8853241B2 (en) 2007-11-21 2014-10-07 Abbvie Inc. Biaryl substituted azabicyclic alkane derivatives

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JP2003500393A (ja) 2003-01-07
KR20020010670A (ko) 2002-02-04
EP1185513A2 (fr) 2002-03-13
MXPA01012202A (es) 2002-06-21
CA2373789A1 (fr) 2000-11-30
AU4667800A (en) 2000-12-12
BR0011534A (pt) 2002-02-26
WO2000071520A3 (fr) 2001-08-23

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