WO2010071575A1 - Dérivés quaternaires de pipéridine et leurs utilisations - Google Patents

Dérivés quaternaires de pipéridine et leurs utilisations Download PDF

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Publication number
WO2010071575A1
WO2010071575A1 PCT/SE2009/051427 SE2009051427W WO2010071575A1 WO 2010071575 A1 WO2010071575 A1 WO 2010071575A1 SE 2009051427 W SE2009051427 W SE 2009051427W WO 2010071575 A1 WO2010071575 A1 WO 2010071575A1
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dichlorophenyl
piperidin
compound
formula
attached
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PCT/SE2009/051427
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English (en)
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Peter Bernstein
Dean Brown
Bruce Thomas Dembofsky
John P Mccauley
Rebecca Urbanek
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Astrazeneca Ab
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen 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
    • A61P25/18—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
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/36—Opioid-abuse
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/24—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by sulfur atoms to which a second hetero atom is attached
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
    • C07D211/28—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms to which a second hetero atom is attached
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/34—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • This invention generally relates to quaternary piperidine compounds, particularly substituted 3-phenylpiperidine compounds and salts thereof.
  • This invention also relates to pharmaceutical compositions comprising such a compound, uses of such a compound (including, for example, treatment methods and medicament preparations), and processes for making such a compound.
  • the brain contains neurons that communicate with each other through chemical messengers called neurotransmitters.
  • Neurotransmitters are produced by neurons.
  • the cellular membrane of a neuron contains receptors with which the neurotransmitters may interact.
  • Serotonin (SERT), dopamine (DAT), and norepinephrine (NET) neurotransmitters belong to a group of neurotransmitters called the monoamine neurotransmitters .
  • Monoamine neurotransmitters are released into the synaptic cleft between neurons and act by stimulating postsynaptic receptors. Monoamine neurotransmitters are removed (or inactivated) primarily by reuptake into presynaptic terminals. In various diseases and/or conditions where neurotransmitters are out of balance, reuptake of a particular neurotransmitter can be inhibited to improve a patient's condition and/or the disease from which the patient suffers.
  • SSRIs serotonin reuptake inhibitors
  • SNRIs norepinephrine reuptake inhibitors
  • SSRIs and SNRIs are generally no more efficacious than monoamine oxidase inhibitors and tricyclic antidepressants, although they do pose less serious side effect risks. Nevertheless, tricyclic antidepressants continue to be used to treat depression.
  • Nomifensine marketed in late 1970's by Hoescht, was an effective motivating and anxiolytic drug reported to be a selective NET:DAT reuptake inhibitor.
  • the unique NET:DAT reuptake inhibitor profile of nomifensine was thought to confer a unique therapeutic benefit to melancholic depressive patients.
  • Nomifensine was, however, withdrawn from the market in 1980 in the wake of nomifensine-associated immune reactions appearing in the literature, several cases of autoimmune haemolytic anaemia, and some deaths.
  • the prevailing theory suggests a reactive metabolite of nomifensine forms a complex with proteins on red blood cells (RBC) to initiate an auto-immune complex.
  • RBC red blood cells
  • This invention comprises, inter alia, piperidine compounds; methods of treatment using the piperidine compounds ⁇ e.g., uses of the piperidine compounds to treat various psychiatric disorders and as pharmacological tools); use of the piperidine compounds to make medicaments; compositions comprising the piperidine compounds ⁇ e.g., pharmaceutical compositions); methods for manufacturing the piperidine compounds; and intermediates used in such manufacturing methods.
  • R 1 and R 2 are each independently selected halogen.
  • R 3 and R 4 are each independently selected from H, -OH, and Ci_ 3 alkyl.
  • R 3 and R 4 together with the carbon to which they are both attached, form C 3 _ 6 Cycloalkyl.
  • R 6 is Ci-Cealkyl.
  • R 7 and R 8 are each independently selected from H and Ci-C ⁇ alkyl.
  • R 9 is selected from H, Ci-C 6 alkyl, -NR 7 R 8 , and haloalkyl.
  • R 10 and R 11 are each independently selected from H and Ci-C ⁇ alkyl.
  • R 12 is selected from H, C r C 6 alkyl, and haloalkyl.
  • n is selected from zero and 1.
  • p is selected from zero, 1, 2, and 3. p, however, is not zero when R 5 is -OR 7 .
  • the compound of Formula (I) is not 2-((R)-3-(3,4- dichlorophenyl)piperidin-3-yl)ethanol. In some embodiments, the compound of Formula (I) is not any enantiomer of 2-(3-(3,4-dichlorophenyl)piperidin-3-yl)ethanol or mixture thereof.
  • This invention also is directed, in part, to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use as a medicament.
  • This invention also is directed, in part, to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for the treatment of a disorder comprising a psychiatric disorder.
  • This invention also is directed, in part, to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for the treatment of a disorder comprising a disorder selected from major depressive disorders, attention-deficit and disruptive behavior disorders, and cocaine-related disorders.
  • This invention also is directed, in part, to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for the treatment of a disorder comprising a disorder selected from atypical depression, melancholy depression, cocaine abuse, and attention deficit hyperactivity disorder.
  • This invention also is directed, in part, to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for the treatment of a disorder comprising a disorder in which modulating norepinephrine transport receptors and/or dopamine transport receptors is beneficial.
  • This invention also is directed, in part, to a use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament.
  • the medicament is for the treatment of a disorder comprising a psychiatric disorder.
  • the medicament is for the treatment of a disorder comprising a disorder selected from major depressive disorders, attention-deficit and disruptive behavior disorders, and cocaine-related disorders.
  • the medicament is for the treatment of a disorder comprising a disorder selected from atypical depression, melancholy depression, cocaine abuse, and attention deficit hyperactivity disorder.
  • the medicament is for the treatment of a disorder comprising a disorder in which modulating norepinephrine transport receptors and/or dopamine transport receptors is beneficial.
  • composition comprises a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • composition also comprises a pharmaceutically acceptable carrier or diluent.
  • This invention also is directed, in part, to a method for treating a disorder in a warm-blooded animal in need of such treatment.
  • the method comprises administering to the animal a therapeutically effective amount a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • the disorder comprises a psychiatric disorder.
  • the disorder comprises a disorder selected from major depressive disorders, attention-deficit and disruptive behavior disorders, and a cocaine-related disorders.
  • the disorder comprises a disorder selected from melancholy depression, atypical depression, cocaine abuse, and ADHD.
  • the disorder comprises a major depressive disorder.
  • the disorder comprises a disorder in which modulating norepinephrine transport receptors and/or dopamine transport receptors is beneficial.
  • This invention also is directed, in part, to a method for modulating norepinephrine transport receptors and/or dopamine transport receptors using a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • R 1 and R 2 are each independently selected halogen.
  • R 1 is chlorine
  • R 1 is fluorine
  • R 2 is chlorine
  • R 2 is fluorine
  • R 1 and R 2 are each independently selected from chlorine and fluorine.
  • R 1 is ⁇ rt/zosubstituted, i.e., R 1 is at the ortho position of the depicted phenyl such that the compound of Formula (I) corresponds to:
  • R 1 is chlorine. In other embodiments, R 1 is fluorine.
  • R 1 is meto-substituted, i.e., R 1 is at the meta position of the depicted phenyl such that the compound of Formula (I) corresponds to:
  • R 1 is chlorine. In other embodiments, R 1 is fluorine.
  • R 1 is p ⁇ ra-substituted, i.e. , R 1 is at the para position of the depicted phenyl such that the compound of Formula (I) corresponds to:
  • R 1 is chlorine. In other embodiments, R 1 is fluorine.
  • n is zero such that no R 2 exists and the compound of Formula (I) corresponds to:
  • R 1 is chlorine. In other embodiments, R 1 is fluorine.
  • n 1 such that the compound of Formula (I) corresponds to:
  • n is 1
  • R 1 and R 2 are each independently selected from chlorine and fluorine.
  • n is 1, and R 1 and R 2 are each chlorine.
  • n is 1, and R 1 and R 2 are each fluorine.
  • n is 1, one of R 1 and R 2 is chlorine, and the other of R 1 and R 2 is fluorine.
  • n is 1, R 1 is at the /? ⁇ ra-position of the phenyl, and R 2 is at the meto-position of the phenyl such that the compound corresponds to:
  • R 1 and R 2 are each chlorine. In other embodiments, R 1 and R 2 are each fluorine. In other embodiments R 1 is chlorine, and R 2 is fluorine. And in other embodiments, R 1 is fluorine, and R 2 is chlorine.
  • n is 1, R 1 is at the meta-position of the phenyl, and R 2 is at the other meto-position of the phenyl such that the compound corresponds to:
  • R 1 and R 2 are each chlorine. In other embodiments, R 1 and R 2 are each fluorine. And in other embodiments R 1 is chlorine, and R 2 is fluorine.
  • p is selected from zero, 1, 2, and 3.
  • p is zero such that the compound of Formula (I) corresponds to:
  • R 5 is not -OR 7 .
  • p is 1 such that the compound of Formula (I) corresponds to:
  • p is 2 such that the compound of Formula (I) corresponds to:
  • p is 3 such that the compound of Formula (I) corresponds to:
  • each R can be the same or different from the other R 3 's, and each R 4 can be the same or different from the other R 4 's.
  • R 3 and R 4 are each independently selected from H, -OH, and Chalky!. [68] In some embodiments, R 3 and R 4 are each independently selected from H, -OH, and CH 3 .
  • R 3 and R 4 are each H.
  • R 3 and R 4 together with the carbon to which they are both attached, form C 3 _ 6 Cycloalkyl.
  • R 5 is -NR 7 R 8 .
  • R 5 is
  • R 6 is Ci-Cealkyl.
  • R 6 is methyl.
  • R 6 is 2-methylpropan-2-yl.
  • R 7 and R 8 are each independently selected from H and Ci-C ⁇ alkyl.
  • R 7 and R 8 are each independently selected from H and Ci_6alkyl, wherein the Ci-C ⁇ alkyl is substituted by 1 or 2 substituents selected from haloalkyl, -C(O)NR 10 R 1 ⁇ -OH, -CN, and -Ci-C 3 alkoxy.
  • R 7 is Ci_6alkyl substituted with haloalkyl. [88] In some embodiments, R 7 is C ⁇ alkyl substituted with -OH.
  • R 8 is hydrogen
  • R 7 and R 8 are each independently selected Ci_6alkyl substituted with haloalkyl.
  • R 7 is C ⁇ alkyl substituted with haloalkyl
  • R 8 is hydrogen
  • R 7 and R 8 are each independently selected Ci_6alkyl substituted with -OH.
  • R 7 is C ⁇ alkyl substituted with -OH, and R 8 is hydrogen.
  • R 7 and R 8 are each independently selected from hydrogen and Ci_ 6 alkyl.
  • R 7 and R 8 are each hydrogen. [96] In some embodiments, R 7 and R 8 are each independently selected Ci_6alkyl. [97] In some embodiments, any Ci_6alkyl of R 7 and R 8 in the above embodiments is a Ci_3alkyl. In some such embodiments, any Csalkyl is selected from n- propyl and wo-propyl. In other embodiments, any Csalkyl is w-propyl. And in other embodiments, any Csalkyl is wo-propyl.
  • R 9 is selected from H, Ci-C 6 alkyl, -NR 7 R 8 , and haloalkyl.
  • R 9 is selected from Ci-C ⁇ alkyl, -NR 7 R 8 , and haloalkyl.
  • R 9 is Ci-C ⁇ alkyl. [102] In some embodiments, R 9 is Ci-C3alkyl. [103] In some embodiments, R 9 is -NR 7 R 8 .
  • R 9 is haloalkyl
  • R 9 is selected from methyl, -N(CHs) 2 , and CF3.
  • R 10 and R 11 are each independently selected from H and Ci-C ⁇ alkyl.
  • R 10 and R 11 are each H.
  • R 10 and R 11 are each independently selected
  • R 10 and R 11 are each methyl.
  • R 12 is selected from H, Ci-C 6 alkyl, and haloalkyl.
  • R 12 is H.
  • R 12 is selected from Ci-C ⁇ alkyl and haloalkyl.
  • R 12 is Ci-C ⁇ alkyl. [114] In some embodiments, R 12 is Ci-C3alkyl. [115] In some embodiments, R 12 is haloalkyl. [116] In some embodiments, R 12 is selected from CH3 and CF3. [117] In some embodiments, R 12 is CH3.
  • R 12 is CF3.
  • the compound of Formula (I) is not 2-((R)-3- (3,4-dichlorophenyl)piperidin-3-yl)ethanol. In some embodiments, the compound of Formula (I) is not any enantiomer of 2-(3-(3,4-dichlorophenyl)piperidin-3-yl)ethanol or mixture thereof.
  • the compound corresponds in structure to Formula (IA):
  • the compound corresponds in structure to Formula
  • All the compounds of this invention include at least one chiral carbon, i.e., the carbon of the piperidinyl that is linked to the phenyl.
  • the structure or name is intended to encompass any single chiral isomer corresponding to that structure or name, as well as any mixture of chiral isomers ⁇ e.g., the racemate).
  • Formula (I) which does not indicate the chirality, is intended to encompass any single isomer corresponding to the structure, as well as any mixture of chiral isomers.
  • a single chiral isomer is obtained by isolating it from a mixture of isomers (e.g., a racemate) using, for example, chiral chromatographic separation.
  • a single chiral isomer is obtained through direct synthesis from, for example, a chiral starting material.
  • the invention is directed to a compound selected from the following (or a salt thereof, particularly a pharmaceutically acceptable salt thereof):
  • the salts of the compounds of this invention are typically acid addition salts.
  • an acid addition salt can be prepared using various inorganic or organic acids.
  • Such salts can typically be formed by, for example, mixing the compound with an acid (e.g., a stoichiometric amount of acid) using various methods known in the art. This mixing may occur in water, an organic solvent (e.g., ether, ethyl acetate, ethanol, isopropanol, or acetonitrile), or an aqueous/organic mixture.
  • a salt may be advantageous due to one or more of its chemical or physical properties, such as stability in differing temperatures and humidities, or a desirable solubility in water, oil, or other solvent.
  • a salt may be used to aid in the isolation or purification of the compound.
  • the salt is pharmaceutically acceptable.
  • Examples of inorganic acids that typically may be used to form acid addition salts include hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric, and phosphoric acid.
  • Examples of organic acids include, for example, aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids.
  • organic salts include cholate, sorbate, laurate, acetate, trifluoroacetate, formate, propionate, succinate, glycolate, gluconate, digluconate, lactate, malate, tartaric acid (and derivatives thereof, e.g., dibenzoyltartrate), citrate, ascorbate, glucuronate, maleate, fumarate, pyruvate, aspartate, glutamate, benzoate, anthranilic acid, mesylate, stearate, salicylate, p-hydroxybenzoate, phenylacetate, mandelate (and derivatives thereof), embonate (pamoate), ethanesulfonate, benzenesulfonate, pantothenate, 2-hydroxyethanesulfonate, sulfanilate, cyclohexylaminosulfonate, algenic acid, ⁇ -hydroxybutyric acid, galactarate, galactur
  • the salt comprises a hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, methanesulphonate, or /7-toluenesulphonate salt.
  • the salt comprises a citric acid salt.
  • the salt comprises an HCl salt.
  • the salt comprises an acetic acid salt.
  • Base-addition salts also are contemplated for some of the compounds of this invention.
  • an alkali metal such as sodium, potassium, or lithium
  • an alkaline earth metal such as a calcium
  • an alkali metal or alkaline earth metal hydroxide or alkoxide e.g., an ethoxide or methoxide
  • a suitably basic organic amine e.g., a choline or meglumine
  • an amine of a compound of Formula I or a salt thereof may form an N-oxide.
  • Such an N-oxide is intended to be encompassed by the compounds of Formula I and salts thereof.
  • An N-oxide can generally be formed by treating an amine with an oxidizing agent, such as hydrogen peroxide or a per-acid (e.g., a peroxycarboxylic acid). See, e.g., Advanced Organic Chemistry, by Jerry March, 4 th Edition, Wiley Interscience.
  • N-oxides also can be made by reacting the amine with m- chloroperoxybenzoic acid (m-CPBA), for example, in an inert solvent, such as dichloromethane. See L. W. Deady, Syn. Comm., 1, pp. 509-514 (1977).
  • the compounds of this invention and salts thereof could form isolatable atropisomers in certain solvents at certain temperatures.
  • the compounds of Formula (I) and salts thereof are intended to encompass any such atropisomers. Atropisomers can generally be isolated using chiral LC.
  • the compounds of Formula (I) and salts thereof are intended to encompass any isotopically-labeled (or "radio-labeled") derivatives of a compound of Formula (I) or salt thereof.
  • Such a derivative is a derivative of a compound of Formula (I) or salt thereof wherein one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature.
  • radionuclides examples include 2 H (also written as “D” for deuterium), 3 H (also written as “T” for tritium), 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 18 F, 35 S, 36 Cl, 82 Br, 75 Br, 76 Br, 77 Br, 123 1, 124 1, 125 I, and 131 L.
  • the radionuclide that is used will depend on the specific application of that radio-labeled derivative. For example, for in vitro receptor labeling and competition assays, 3 H or 14 C are often useful. For radio-imaging applications, 11 C or 18 F are often useful.
  • the radionuclide is 3 H.
  • the radionuclide is 14 C.
  • the radionuclide is 11 C.
  • the radionuclide is 18 F.
  • the compounds of Formula (I) and salts thereof are intended to cover all solid state forms of the compounds and salts.
  • the compounds of Formula (I) and salts thereof also are intended to encompass all solvated (e.g., hydrated) and unsolvated forms of the compounds and salts.
  • the compounds of Formula (I) and salts thereof also are intended to encompass coupling partners in which a compound of Formula (I) or a salt thereof is linked to a coupling partner by, for example, being chemically coupled to the compound or salt or physically associated with it.
  • coupling partners include a label or reporter molecule, a supporting substrate, a carrier or transport molecule, an effector, a drug, an antibody, or an inhibitor.
  • Coupling partners can be covalently linked to a compound or salt via an appropriate functional group on the compound, such as a hydroxyl, carboxyl, or amino group.
  • Other derivatives include formulating a compound or salt with liposomes.
  • This invention provides, in part, for methods to treat various disorders in animals, particularly mammals.
  • Mammals include, for example, humans. Mammals also include, for example, companion animals (e.g., dogs, cats, and horses), livestock animals (e.g., cattle and swine); lab animals (e.g., mice and rats); and wild, zoo, and circus animals (e.g., bears, lions, tigers, apes, and monkeys).
  • the compounds and salts of this invention may generally be used to treat a range of disorders in which modulating the norepinephrine transport receptor and/or dopamine transport receptor is beneficial. Accordingly, this invention is directed, in part, to a method of using a compound of Formula (I) or salt thereof for treating a norepinephrine transport receptor and/or dopamine transport receptor associated condition therewith.
  • a compound or salt of this invention is used to modulate at least one norepinephrine transport receptor and/or dopamine transport receptor.
  • modulate means the activation (i.e., act as an agonist) or inhibition (i.e., act as antagonist) of the norepinephrine transport receptor and/or dopamine transport receptor.
  • the terms “modulate”, “modulates”, “modulating”, or “modulation” mean the inhibition of at least one norepinephrine transport receptor and/or dopamine transport receptor.
  • the compound or salt thereof exhibits a Ki value of less than about 1.5 ⁇ M toward NET and/or DAT using an assay described below in the Example 118. In some embodiments, the compound or salt thereof exhibits a Ki value of from about 0.1 nM to about 1.5 ⁇ M toward NET and/or DAT. In some embodiments, the compound or salt exhibits a Ki value of from about 0.1 nM to about 700 nM toward NET and/or DAT. In some embodiments, the compound or salt exhibits a Ki value of from about 0.1 nM and 200 nM toward NET and/or DAT.
  • the compound or salt exhibits a Ki value of from about 0.1 nM and 100 nM toward NET and/or DAT. In some embodiments, the compound or salt exhibits a Ki value of less than about 1200 nM toward NET and/or DAT. In some embodiments, the compound or salt exhibits a Ki value of less than about 100 nM toward NET and/or DAT. In some embodiments, the compound or salt exhibits a Ki value of less than about 50 nM toward NET and/or DAT. And in some embodiments, the compound or salt exhibits a Ki value of less than about 10 nM toward NET and/or DAT.
  • a compound or salt of this invention is administered to an animal in which the modulation of at least one norepinephrine transport receptor and/or dopamine transport receptor in the animal is beneficial to the animal for treating a disorder.
  • the compound or salt is normally administered to the animal in the form of a pharmaceutical composition that also comprises at least one carrier, diluent, or excipient.
  • a compound or salt of this invention is administered to an animal to treat a psychiatric disorder in the animal.
  • Psychiatric disorders include, for example: (1) mood disorder(s), such as, for example:
  • depressive disorder(s) such as major depressive disorder(s) (e.g., melancholy depression and atypical depression) and dysthymic disorder(s)
  • bipolar depression and/or bipolar mania such as, for example, bipolar I (bipolar disorders with manic, depressive or mixed episodes) and bipolar II,
  • mood disorder(s) due to a general medical condition (2) attention-deficit and disruptive behavior disorder(s), such as, for example, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), and affective disorders; and (3) substance-related disorder(s), such as, for example, substance dependence; substance abuse; substance intoxication; substance withdrawal; alcohol-related disorder(s); amphetamine (or amphetamine-like)-related disorder(s); caffeine-related disorder(s); cannabis-related disorder(s); cocaine-related disorder(s) (e.g.; cocaine abuse); hallucinogen-related disorder(s); inhalant-related disorder(s); nicotine-related disorder(s)s; opioid-related disorder(s)s; phencyclidine (or phencyclidine-like)-related disorder(s); and sedative-, hypnotic- or anxiolytic-related disorder(s).
  • attention-deficit and disruptive behavior disorder(s) such as, for example, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), and affective disorders
  • a compound or salt of this invention (generally a therapeutically effective amount) is used for therapy.
  • a compound or salt of this invention is used to treat a major depressive disorder.
  • the compound or salt is administered (generally a therapeutically effective amount) to an animal to treat a major depressive disorder in the animal.
  • the disorder comprises melancholy depression. In other embodiments, the disorder comprises atypical depression.
  • a compound or salt of this invention is used to treat an attention-deficit or disruptive behavior disorder.
  • the compound or salt is administered (generally a therapeutically effective amount) to an animal to treat an attention-deficit or disruptive behavior disorder in the animal.
  • the disorder comprises ADHD.
  • a compound or salt of this invention is used to treat a cocaine-related disorder.
  • the compound or salt is administered (generally a therapeutically effective amount) to an animal to treat a cocaine-related disorder in the animal.
  • the disorder comprises cocaine abuse.
  • a compound or salt of this invention is used to make a medicament (i.e., a pharmaceutical composition).
  • the pharmaceutical composition comprises a therapeutically effective amount of the compound or salt.
  • Pharmaceutical compositions comprising a compound or salt of this invention can vary widely. Although it is contemplated that a compound or salt of this invention could be administered by itself (i.e., without any other active or inactive ingredient), the pharmaceutical composition normally will instead comprise one or more additional active ingredients and/or inert ingredients.
  • carriers diluents, and excipients.
  • Methods for making pharmaceutical compositions and the use of carriers, diluents, and excipients are well known in the art. See, e.g., for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, 15th Edition, 1975.
  • a compound or salt of this invention (generally a therapeutically effective amount) is used to make a medicament for treating a major depressive disorder.
  • the disorder comprises melancholy depression.
  • the disorder comprises atypical depression.
  • a compound or salt of this invention (generally a therapeutically effective amount) is used to make a medicament for treating a cocaine-related disorder.
  • the disorder comprises cocaine abuse.
  • a compound or salt of this invention (generally a therapeutically effective amount) is used to make a medicament for treating an attention-deficit or disruptive behavior disorder.
  • the disorder comprises ADHD.
  • compositions comprising a compound or salt of this invention may be formulated for a variety of suitable routes and means of administration, including oral, rectal, nasal, topical, buccal, sublingual, vaginal, inhalation, insufflation, or parenteral administration.
  • the compound or salt is administered orally.
  • the compound or salt is administered intravenously.
  • the compound or salt is administered intramuscularly.
  • the compound or salt is administered subcutaneously.
  • the compound or salt is administered intraperitoneally, intrathoracially, epidurally, intrathecally, intracerebroventricularly, and injection into the joints.
  • compositions of this invention may, for example, be in the form of solids, aqueous or oily solutions, suspensions, emulsions, creams, ointments, mists, gels, nasal sprays, suppositories, finely divided powders, and aerosols or nebulisers for inhalation.
  • the composition comprises a solid or liquid dosage form that may be administered orally.
  • Solid form compositions may include, for example, powders, tablets, dispersible granules, capsules, cachets, and suppositories.
  • a solid carrier may comprise one or more substances. Such substances are generally inert.
  • a carrier also may act as, for example, a diluent, flavoring agent, solubilizer, lubricant, preservative, stabilizer, suspending agent, binder, or disintegrating agent. It also may act as, for example, an encapsulating material.
  • suitable carriers include pharmaceutical grade mannitol, lactose, magnesium carbonate, magnesium stearate, talc, lactose, sugar (e.g., glucose and sucrose), pectin, dextrin, starch, tragacanth, cellulose, cellulose derivatives (e.g., methyl cellulose and sodium carboxymethyl cellulose), sodium saccharin, low-melting wax, and cocoa butter.
  • the carrier is typically a finely divided solid, which is in a mixture with the finely divided active component.
  • the active component is typically mixed with the carrier having the desirable binding properties in suitable proportions and compacted into the desired shape and size.
  • a low-melting wax e.g., a mixture of fatty acid glycerides and cocoa butter
  • the molten homogeneous mixture is then poured into convenient-sized molds and allowed to cool and solidify.
  • non-irritating excipients examples include, for example, cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights, and fatty acid esters of polyethylene glycol.
  • Liquid compositions can be prepared by, for example, dissolving or dispersing the compound or a salt of this invention in a carrier, such as, for example, water, water/propylene glycol solutions, saline aqueous dextrose, glycerol, or ethanol.
  • aqueous solutions for oral administration can be prepared by dissolving a compound or salt of this invention in water with a solubilizer (e.g., a polyethylene glycol).
  • a solubilizer e.g., a polyethylene glycol
  • aqueous suspensions for oral use can be made by dispersing the compound or salt of this invention in a finely divided form in water, together with a viscous material, such as, for example, one or more natural synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, or other suspending agents.
  • a viscous material such as, for example, one or more natural synthetic gums, resins, methyl cellulose, sodium carboxymethyl cellulose, or other suspending agents.
  • the liquid composition also may contain other non-toxic auxiliary inert ingredients, such as, for example, wetting or emulsifying agents, pH buffering agents and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine sodium acetate, sorbitan monolaurate, triethanolamine oleate, etc.
  • compositions also may contain other ingredients, such as, for example, one or more pharmaceutical adjuvants.
  • the pharmaceutical composition comprises from about 0.05% to about 99% (by weight) of a compound or salt of this invention. In some such embodiments, for example, the pharmaceutical composition comprises from about 0.10% to about 50% (by weight) of a compound or salt of this invention.
  • a "therapeutically effective amount" is an amount sufficient to reduce or completely alleviate symptoms or other detrimental effects of the disorder; cure the disorder; reverse, completely stop, or slow the progress of the disorder; reduce the risk of the disorder getting worse; or delay or reduce the risk of onset of the disorder.
  • the optimum dosage and frequency of administration will depend on the particular condition being treated and its severity; the species of the patient; the age, sex, size and weight, diet, and general physical condition of the particular patient; brain/body weight ratio; other medication the patient may be taking; the route of administration; the formulation; and various other factors known to physicians (in the context of human patients), veterinarians (in the context of non-human patients), and others skilled in the art.
  • the optimum amount of a compound or salt of this invention is from about 0.05 to about 300 mg/kg body weight per day. In other embodiments, the optimum amount is less than about 200 mg/kg body weight per day. In other embodiments, the optimum amount is from about 1 to about 1000 mg/kg body weight per day, or from about 1 to about 100 mg/kg body weight per day (e.g., about 15 mg/kg body weight per day).
  • the pharmaceutical compositions can be in one or more unit dosage forms. Accordingly, the composition may be divided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be, for example, a capsule, cachet, or tablet itself, or it can be the appropriate number of any of these in packaged forms.
  • the unit dosage form alternatively can be a packaged preparation in which the package contains discrete quantities of the composition, such as, for example, packeted tablets, capsules, or powders in vials or ampoules.
  • Unit dosage forms may be prepared by, for example, various methods well known in the art of pharmacy.
  • a dosage can be given once daily or in divided doses, such as, for example, from 2 to 4 times per day.
  • the dose is conventionally formulated in an oral dosage form by compounding from about 5 to about 250 mg per unit of dosage with, for example, one or more inert or active ingredients using accepted pharmaceutical practices.
  • a compound or salt of this invention is administered concurrently, simultaneously, sequentially, or separately with one or more other pharmaceutically active compounds.
  • the other pharmaceutically active compound(s) is/are selected from the following:
  • Antidepressants which are contemplated to include, for example, one or more of agomelatine, amitriptyline, amoxapine, bupropion, citalopram, clomipramine, desipramine, doxepin duloxetine, elzasonan, escitalopram, fluvoxamine, fluoxetine, gepirone, imipramine, ipsapirone, maprotiline, mirtazeprine, nortriptyline, nefazodone, paroxetine, phenelzine, protriptyline, ramelteon, reboxetine, robalzotan, selegiline, sertraline, sibutramine, thionisoxetine, tranylcypromaine, trazodone, trimipramine, venlafaxine and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof.
  • Antipsychotics which are contemplated to include, for example, one or more of quetiapine and pharmaceutically active isomer(s) and metabolite(s) thereof; and amisulpride, aripiprazole, asenapine, benzisoxidil, bifeprunox, carbamazepine, clozapine, chlorpromazine, debenzapine, dibenzapine, divalproex, droperidol, duloxetine, eszopiclone, fluphenazine, haloperidol, iloperidone, lamotrigine, lithium, loxapine, mesoridazine, molindone, olanzapine, paliperidone, perlapine, perphenazine, phenothiazine, phenylbutylpiperidine, pimozide, prochlorperazine, risperidone, sertindole, sulpir
  • Anxiolytics which are contemplated to include, for example, one or more of alnespirone, azapirones, benzodiazepines, barbiturates such as adinazolam, alprazolam, balezepam, bentazepam, bromazepam, brotizolam, buspirone, clonazepam, clorazepate, chlordiazepoxide, cyprazepam, diazepam, diphenhydramine, estazolam, fenobam, flunitrazepam, flurazepam, fosazepam, lorazepam, lormetazepam, meprobamate, midazolam, nitrazepam, oxazepam, prazepam, quazepam, reclazepam, suriclone, tracazolate, trepipam, temazepam, triazolam,
  • Parkinson's therapies and agents for the treatment of extrapyramidal symtpoms which are contemplated to include, for example, one or more of levodopa, carbidopa, amantadine, pramipexole, ropinirole, pergolide, cabergoline, apomorphine, bromocriptine, MAOB inhibitors (e.g., selegine and rasagiline), COMT inhibitors (e.g., entacapone and tolcapone), alpha-2 inhibitors, anticholinergics (e.g., benztropine, biperiden, orphenadrine, procyclidine, and trihexyphenidyl), dopamine reuptake inhibitors, NMDA antagonists, Nicotine agonists, Dopamine agonists, and inhibitors of neuronal nitric oxide synthase, and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof.
  • MAOB inhibitors e
  • Migraine therapies which are contemplated to include, for example, one or more of almotriptan, amantadine, bromocriptine, butalbital, cabergoline, dichloralphenazone, eletriptan, frovatriptan, lisuride, naratriptan, pergolide, pramipexole, rizatriptan, ropinirole, sumatriptan, zolmitriptan, zomitriptan, and equivalents, and pharmaceutically active isomer(s) and metabolite(s) thereof.
  • Stroke therapies which are contemplated to include, for example, one or more of abciximab, activase, disufenton sodium, citicoline, crobenetine, desmoteplase,repinotan, traxoprodil, and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof.
  • Urinary incontinence therapies which are contemplated to include, for example, one or more of darafenacin, dicyclomine, falvoxate, imipramine, desipramine, oxybutynin, propiverine, propanthedine, robalzotan, solifenacin, alfazosin, doxazosin, terazosin, tolterodine, and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof.
  • Neuropathic pain therapies which are contemplated to include, for example, one or more of gabapentin, lidoderm, pregablin, and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof.
  • Nociceptive pain therapies which are contemplated to include, for example, one or more of celecoxib, cideine, etoricoxib, fentanyl, hydrocodone, hydromorphone, levo-alpha-acetylmethadol, lumiracoxib, meperidine, methadone, morphine, oxycodone, rofecoxib, valdecoxib, diclofenac, loxoprofen, naproxen, paracetamol, propoxyphene, sufentanyl, and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof.
  • Insomnia therapies which are contemplated to include, for example, one or more of allobarbital, alonimid, amobarbital, benzoctamine, butabarbital, capuride, chloral, cloperidone, clorethate, dexclamol, estazolam, eszopicline, ethchlorvynol, etomidate, flurazepam, glutethimide, halazepam, hydroxyzine, mecloqualone, melatonin, mephobarbital, methaqualone, midaflur, midazolam, nisobamate, pagoclone, pentobarbital, perlapine, phenobarbital, propofol, quazepam, ramelteon, roletamide, suproclone, temazepam, triazolam, triclofos,secobarbital, zaleplon, Zolp
  • Mood stabilizers which are contemplated to include, for example, one or more of carbamazepine, divalproex, gabapentin, lamotrigine, lithium, olanzapine, quetiapine, valproate, valproic acid, verapamil, and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof.
  • Medications for treating obesity such as, for example, orlistat, sibutramine, rimonabant, and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof.
  • Agents for treating ADHD which are contemplated to include, for example, one or more of amphetamine, methamphetamine, dextroamphetamine, atomoxetine, methylphenidate, dexmethylphenidate, modafmil, and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof.
  • Agents used to treat substance abuse disorders, dependence, and withdrawal which are contemplated to include, for example, one or more of nicotine replacement therapies (e.g., gum, patches, and nasal spray); nicotinergic receptor agonists, partial agonists, and antagonists, (e.g., varenicline); acomprosate; bupropion; clonidine; disulf ⁇ ram; methadone; naloxone; naltrexone; and equivalents and pharmaceutically active isomer(s) and metabolite(s) thereof.
  • nicotine replacement therapies e.g., gum, patches, and nasal spray
  • nicotinergic receptor agonists, partial agonists, and antagonists e.g., varenicline
  • acomprosate bupropion
  • clonidine clonidine
  • disulf ⁇ ram methadone
  • naloxone naltrexone
  • the other pharmaceutically active ingredient(s) comprises a cognitive enhancing agent.
  • the other pharmaceutically active ingredient(s) comprises a memory enhancing agent.
  • the other pharmaceutically active ingredient(s) comprises a choline esterase inhibitor.
  • the other pharmaceutically active ingredient(s) comprises anti-inflammatory agent.
  • the antipsychotic comprises an atypical antipsychotic agent.
  • Atypical antipsychotic agents include, for example, olanzapine (marketed as Zyprexa), aripiprazole (marketed as Ability), risperidone (marketed as Risperdal), quetiapine (marketed as Seroquel), clozapine (marketed as Clozaril), ziprasidone (marketed as Geodon), and olanzapine/fluoxetine (marketed as Symbyax).
  • the other pharmaceutically active ingredient(s) comprises a selective serotonin reuptake inhibitor (or "serotonin-specific reuptake inhibitor” or SSRI").
  • a selective serotonin reuptake inhibitor or "serotonin-specific reuptake inhibitor” or SSRI”
  • Such agents include, for example, fluoxetine (marketed as, for example, Prozac), paroxetine (marketed as, for example, Paxil), citalopram (marketed as, for example, Celexa), dapoxetine, mesembrine, excitalopram (marketed as, for example, Lexapro), fluvoxamine (marketed as, for examle, Luvox), zimelidine (marketed as, for example, Zelmid), and sertraline (marketed as, for example, Zoloft).
  • fluoxetine marketed as, for example, Prozac
  • paroxetine marketed as, for example, Paxil
  • citalopram marketed as, for example, Celexa
  • a compound or salt of this invention is administered as part of a combination therapy with chemotherapy.
  • the amount of the compound or salt of this invention and the amount of the other pharmaceutically active agent(s) are, when combined, therapeutically effective to treat a targeted disorder in the animal patient.
  • the combined amounts are "therapeutically effective amount” if they are, when combined, sufficient to reduce or completely alleviate symptoms or other detrimental effects of the disorder; cure the disorder; reverse, completely stop, or slow the progress of the disorder; reduce the risk of the disorder getting worse; or delay or reduce the risk of onset of the disorder.
  • such amounts may be determined by one skilled in the art by, for example, starting with the dosage range described in this patent for the compound or salt of this invention and an approved or otherwise published dosage range(s) of the other pharmaceutically active compound(s).
  • compositions When used in a combination therapy, it is contemplated that the compound or salt of this invention and the other active ingredients may be administered in a single composition, completely separate compositions, or a combination thereof. It also is contemplated that the active ingredients may be administered concurrently, simultaneously, sequentially, or separately.
  • the particular composition(s) and dosing frequency(ies) of the combination therapy will depend on a variety of factors, including, for example, the route of administration, the condition being treated, the species of the patient, any potential interactions between the active ingredients when combined into a single composition, any interactions between the active ingredients when they are administered to the animal patient, and various other factors known to physicians (in the context of human patients), veterinarians (in the context of non-human patients), and others skilled in the art.
  • a compound in accordance with Formula (III) can be obtained by treating an appropriate amine compound in accordance with Formula (II) with an appropriate acylating agent, such as, for example, di-tert-butyl dicarbonate in an appropriate solvent, such as, for example, THF.
  • an appropriate acylating agent such as, for example, di-tert-butyl dicarbonate
  • an appropriate solvent such as, for example, THF.
  • a compound in accordance with Formula (IV) can be obtained by treating a compound in accordance with Formula (III) with an appropriate acylating agent, such as, for example, dimethylcarbamoyl chloride in an appropriate solvent, such as, for example, pyridine.
  • an appropriate acylating agent such as, for example, dimethylcarbamoyl chloride
  • an appropriate solvent such as, for example, pyridine.
  • a compound in accordance with Formula (I) can be obtained by treating a compound in accordance with Formula (IV) with an appropriate acid, such as, for example, TFA or HCl in an appropriate solvent, such as, for example, methylene chloride.
  • an appropriate acid such as, for example, TFA or HCl
  • an appropriate solvent such as, for example, methylene chloride.
  • R 1 , R 2 , and R 7 are as defined above; and R 13 is methyl or ethyl.
  • a compound in accordance with Formula (VI) can be obtained by treating an appropriate benzylic halide compound in accordance with Formula (V) with an appropriate alkylating agent, such as, for example, sodium cyanide and an appropriate phase-transfer catalyst, such as, for example, N-benzyl-N,N-diethylethanaminium chloride in an appropriate solvent, such as, for example, chloroform and water.
  • an appropriate alkylating agent such as, for example, sodium cyanide
  • an appropriate phase-transfer catalyst such as, for example, N-benzyl-N,N-diethylethanaminium chloride in an appropriate solvent, such as, for example, chloroform and water.
  • a compound in accordance with Formula (VII) can be obtained by treating a compound in accordance with Formula (VI) with an appropriate base, such as, for example, sodium hydride and an appropriate halide, such as, for example, 2-(2-bromoethoxy)tetrahydro-2H-pyran in an appropriate solvent, such as, for example, THF.
  • an appropriate base such as, for example, sodium hydride and an appropriate halide, such as, for example, 2-(2-bromoethoxy)tetrahydro-2H-pyran in an appropriate solvent, such as, for example, THF.
  • a compound in accordance with Formula (VIII) can be obtained by treating a compound in accordance with Formula (VII) with an appropriate base, such as, for example, lithium diisopropylamide and an appropriate halide, such as, for example, ethyl 3-bromopropanoate, in an appropriate solvent, such as, for example, THF.
  • an appropriate base such as, for example, lithium diisopropylamide and an appropriate halide, such as, for example, ethyl 3-bromopropanoate
  • an appropriate solvent such as, for example, THF.
  • a compound in accordance with Formula (IX) can be obtained by treating a compound in accordance with Formula (VIII) with an appropriate hydrogenation catalyst, such as, for example, Raney Nickel 2800 under H 2 at a pressure of, for example, 50 psig in an appropriate solvent, such as, for example, methanol and ammonium hydroxide at elevated temperature of, for example, 55 0 C.
  • an appropriate hydrogenation catalyst such as, for example, Raney Nickel 2800 under H 2 at a pressure of, for example, 50 psig
  • an appropriate solvent such as, for example, methanol and ammonium hydroxide
  • a compound in accordance with Formula (I) can be obtained by treating a compound in accordance with Formula (IX) with an appropriate reducing agent, such as, for example, BH 3 THF in an appropriate solvent, such as, for example, THF. This intermediate was cooled and an appropriate solvent, such as, for example, methanol, was added. Then, an appropriate acid, such as, for example, hydrochloric acid, was added. The reaction may then be heated at an elevated temperature of, for example, 6O 0 C.
  • an appropriate reducing agent such as, for example, BH 3 THF in an appropriate solvent, such as, for example, THF.
  • an appropriate solvent such as, for example, methanol
  • an appropriate acid such as, for example, hydrochloric acid
  • R 1 and R 2 are as defined above.
  • a compound in accordance with Formula (X) can be obtained by treating an appropriate alcohol compound in accordance with Formula (III) with an appropriate oxidizing agent, such as, for example, pyridinium dichromate, in an appropriate solvent, such as, for example, DMF.
  • an appropriate oxidizing agent such as, for example, pyridinium dichromate
  • a compound in accordance with Formula (XI) can be obtained by treating a compound in accordance with Formula (X) with an appropriate methylating agent, such as, for example, trimethylsilylchloride, in an appropriate solvent, such as, for example, methanol.
  • an appropriate methylating agent such as, for example, trimethylsilylchloride
  • FormulaXII can be obtained by treating a compound in accordance with Formula FormulaXI with an appropriate acylating agent, such as, for example, di-tert-butyl dicarbonate, in an appropriate solvent, such as, for example, THF.
  • an appropriate acylating agent such as, for example, di-tert-butyl dicarbonate
  • an appropriate solvent such as, for example, THF.
  • a compound in accordance with Formula (XIII) can be obtained by treating a compound in accordance with Formula (XII) with an appropriate reagent, such as, for example, methyl magnesium bromide in an appropriate solvent, such as, for example, THF.
  • an appropriate reagent such as, for example, methyl magnesium bromide
  • an appropriate solvent such as, for example, THF.
  • a compound in accordance with Formula (I) can be obtained by treating a compound in accordance with Formula (XIII) with an appropriate acid, such as, for example TFA or HCL in an appropriate solvent, such as, for example, methylene chloride.
  • R 1 and R 2 are as defined above.
  • a compound in accordance with Formula (Ib) and (Ic) can be obtained by treating an appropriate aromatic halide compound in accordance with Formula (I) with an appropriate reducing agent, such as, for example, lithium aluminum hydride, in an appropriate solvent, such as, for example, THF.
  • an appropriate reducing agent such as, for example, lithium aluminum hydride
  • R 1 and R 2 are as defined above.
  • a compound in accordance with Formula (XIV) can be obtained by treating an appropriate alcohol compound in accordance with Formula (III) with an appropriate alkylating agent, such as, for example, methanesulfonyl chloride in the presence of an appropriate base, such as, for example, triethylamine in an appropriate solvent, such as, for example, methylene chloride.
  • an appropriate alkylating agent such as, for example, methanesulfonyl chloride
  • an appropriate base such as, for example, triethylamine
  • an appropriate solvent such as, for example, methylene chloride.
  • a compound in accordance with Formula (XV) can be obtained by treating an appropriate mesylate compound in accordance with Formula (XIV) with an appropriate azide, such as, for example, sodium azide in an appropriate solvent, such as, for example, DMSO. Step 3
  • a compound in accordance with Formula (XVI) can be obtained by treating an appropriate azide compound in accordance with Formula (XV) with an appropriate reducing agent, such as, for example, triphenylphosphine in an appropriate solvent, such as, for example, THF and water.
  • an appropriate reducing agent such as, for example, triphenylphosphine in an appropriate solvent, such as, for example, THF and water.
  • a compound in accordance with Formula (XVII) can be obtained by treating a compound in accordance with Formula (XVI) with an appropriate acylating agent, such as, for example, di-tert-butyl dicarbonate in an appropriate solvent, such as, for example, THF.
  • an appropriate acylating agent such as, for example, di-tert-butyl dicarbonate
  • an appropriate solvent such as, for example, THF.
  • a compound in accordance with Formula (I) can be obtained by treating a compound in accordance with Formula (XVII) with an appropriate acid, such as, for example, TFA or HCl in an appropriate solvent, such as, for example, methylene chloride.
  • an appropriate acid such as, for example, TFA or HCl
  • an appropriate solvent such as, for example, methylene chloride.
  • R 1 , R 2 , R 7 and R 8 are as defined above.
  • a compound in accordance with Formula (XVIII) can be obtained by treating an appropriate mesylate of a compound in accordance with Formula (XIV) with an appropriate alkyl amine, such as, for example, methylamine in an appropriate solvent, such as, for example, THF.
  • an appropriate alkyl amine such as, for example, methylamine
  • an appropriate solvent such as, for example, THF.
  • a compound in accordance with Formula (XIX) can be obtained by treating an appropriate amine of a compound in accordance with Formula (XVIII) with an appropriate aldehyde, such as, for example, 1,5 -dimethyl- lH-pyrazole-3-carbaldehyde in the presence of a suitable dehydrating agent, such as, for example, sodium triacetoxyborohydride in a suitable solvent such as, for example, 1,2-dichloroethane.
  • an appropriate aldehyde such as, for example, 1,5 -dimethyl- lH-pyrazole-3-carbaldehyde
  • a suitable dehydrating agent such as, for example, sodium triacetoxyborohydride
  • a suitable solvent such as, for example, 1,2-dichloroethane.
  • a compound in accordance with Formula (I) can be obtained by treating a compound in accordance with Formula (XIX) with an appropriate acid, such as, for example, TFA or HCl in an appropriate solvent, such as, for example, methylene chloride.
  • an appropriate acid such as, for example, TFA or HCl
  • an appropriate solvent such as, for example, methylene chloride.
  • R 1 , R 2 , R 7 and R 12 are as defined above.
  • a compound in accordance with Formula (XX) can be obtained by treating an appropriate amine of a compound in accordance with Formula (XVII) with an appropriate acylating agent, such as, for example, acetic anhydride in an appropriate solvent, such as, for example, pyridine.
  • an appropriate acylating agent such as, for example, acetic anhydride
  • an appropriate solvent such as, for example, pyridine.
  • a compound in accordance with Formula (I) can be obtained by treating a compound in accordance with Formula (XX) with an appropriate acid, such as, for example, TFA or HCl in an appropriate solvent, such as, for example, methylene chloride.
  • an appropriate acid such as, for example, TFA or HCl
  • an appropriate solvent such as, for example, methylene chloride.
  • R 1 , R 2 , R 7 and R 9 are as defined above.
  • a compound in accordance with Formula (XXI) can be obtained by treating an appropriate amine compound in accordance with Formula (XVII) with an appropriate acylating agent, such as, for example, methanesulfonyl chloride with an appropriate base, such as, for example, triethylamine in an appropriate solvent, such as, for example, 1 ,2-dichloroethane.
  • an appropriate acylating agent such as, for example, methanesulfonyl chloride
  • an appropriate base such as, for example, triethylamine
  • an appropriate solvent such as, for example,2-dichloroethane.
  • a compound in accordance with Formula (I) can be obtained by treating a compound in accordance with Formula (XXI) with an appropriate acid, such as, for example, TFA or HCl in an appropriate solvent, such as, for example, methylene chloride.
  • an appropriate acid such as, for example, TFA or HCl
  • an appropriate solvent such as, for example, methylene chloride.
  • R 1 , R 2 and R 7 are as defined above.
  • a compound in accordance with Formula (XXIII) can be obtained by treating an appropriate acid compound in accordance with Formula (XXII) with an appropriate amine, such as, for example, azetidine in the presence of a suitable dehydrating agent, such as, for example, EDC and a suitable base, such as, for example, diisopropylethylamine in an appropriate solvent, such as, for example, DCM.
  • an appropriate amine such as, for example, azetidine
  • a suitable dehydrating agent such as, for example, EDC
  • a suitable base such as, for example, diisopropylethylamine
  • an appropriate solvent such as, for example, DCM.
  • a compound in accordance with Formula (I) can be obtained by treating a compound in accordance with Formula (XXIII) with an appropriate acid, such as, for example, TFA or HCl in an appropriate solvent, such as, for example, methylene chloride.
  • an appropriate acid such as, for example, TFA or HCl
  • an appropriate solvent such as, for example, methylene chloride.
  • R 1 and R 2 are as defined above.
  • a compound in accordance with Formula (XXV) can be obtained by treating an appropriate mesylate compound in accordance with Formula (XXIV) with an appropriate base, such as, for example, sodium t-butoxide, in an appropriate solvent, such as, for example, DMSO.
  • an appropriate base such as, for example, sodium t-butoxide
  • an appropriate solvent such as, for example, DMSO.
  • a compound in accordance with Formula (I) can be obtained by treating a compound in accordance with Formula (XXV) with an appropriate acid, such as, for example, TFA or HCl in an appropriate solvent, such as, for example, methylene chloride.
  • an appropriate acid such as, for example, TFA or HCl
  • an appropriate solvent such as, for example, methylene chloride.
  • R 1 , R 2 and R 6 are as defined above.
  • a compound in accordance with Formula (XXVI) can be obtained by treating an appropriate mesylate compound in accordance with Formula (XXIV) with an appropriate thiolate, such as, for example, sodium methanethiolate in an appropriate solvent, such as, for example, THF.
  • an appropriate thiolate such as, for example, sodium methanethiolate in an appropriate solvent, such as, for example, THF.
  • a compound in accordance with Formula (I) can be obtained by treating a compound in accordance with Formula (XXVI) with an appropriate acid, such as, for example, TFA or HCl in an appropriate solvent, such as, for example, methylene chloride.
  • an appropriate acid such as, for example, TFA or HCl
  • an appropriate solvent such as, for example, methylene chloride.
  • a compound in accordance with Formula (XXVII) can be obtained by treating an appropriate thiol compound in accordance with Formula (XXVI) with an appropriate oxidizing agent, such as, for example, m-CPBA in an appropriate solvent, such as, for example, 1,2-dichloroethane.
  • an appropriate oxidizing agent such as, for example, m-CPBA
  • an appropriate solvent such as, for example, 1,2-dichloroethane.
  • a compound in accordance with Formula (I) can be obtained by treating a compound in accordance with Formula (XXVII) with an appropriate acid, such as, for example, TFA or HCl in an appropriate solvent, such as, for example, methylene chloride.
  • an appropriate acid such as, for example, TFA or HCl
  • an appropriate solvent such as, for example, methylene chloride.
  • a compound in accordance with Formula (XXVIII) can be obtained by treating an appropriate thiol compound in accordance with Formula (XXVI) with an excess of an appropriate oxidizing agent, such as, for example, m-CPBA in an appropriate solvent, such as, for example, 1,2-dichloroethane.
  • an appropriate oxidizing agent such as, for example, m-CPBA
  • an appropriate solvent such as, for example, 1,2-dichloroethane.
  • a compound in accordance with Formula (I) can be obtained by treating a compound in accordance with Formula (XXVIII) with an appropriate acid, such as, for example, TFA or HCl in an appropriate solvent, such as, for example, methylene chloride.
  • an appropriate acid such as, for example, TFA or HCl
  • an appropriate solvent such as, for example, methylene chloride.
  • R 1 , R 2 and R 7 are as defined above.
  • a compound in accordance with Formula (XXIX) can be obtained by treating an appropriate alcohol compound in accordance with Formula (III) with an appropriate alkylating agent, such as, for example, methyl iodide with a suitable base, such as, for example, sodium hydride in an appropriate solvent, such as, for example, THF.
  • an appropriate alkylating agent such as, for example, methyl iodide
  • a suitable base such as, for example, sodium hydride
  • an appropriate solvent such as, for example, THF.
  • a compound in accordance with Formula (I) can be obtained by treating a compound in accordance with Formula (XXIX) with an appropriate acid, such as, for example, TFA or HCl in an appropriate solvent, such as, for example, methylene chloride.
  • an appropriate acid such as, for example, TFA or HCl
  • an appropriate solvent such as, for example, methylene chloride.
  • R*and R 2 are as defined above.
  • a compound in accordance with Formula (XXX) can be obtained by treating an appropriate mesylate compound in accordance with Formula (XXIV) with an appropriate metal cyanide agent, such as, for example, sodium cyanide, in an appropriate solvent, such as, for example, DMSO.
  • an appropriate metal cyanide agent such as, for example, sodium cyanide
  • a compound in accordance with Formula (I) can be obtained by treating a compound in accordance with Formula (XXX) with an appropriate acid, such as, for example, TFA or HCl in an appropriate solvent, such as, for example, methylene chloride.
  • an appropriate acid such as, for example, TFA or HCl
  • an appropriate solvent such as, for example, methylene chloride.
  • a compound in accordance with Formula (XXXI) can be obtained by treating an appropriate cyano compound in accordance with Formula (XXX) with an appropriate hydrogenation catalyst, such as, for example, Raney Nickel 2800 under H 2 at a pressure of, for example, 50 psig, in an appropriate solvent, such as, for example, methanol and ammonia in methanol.
  • an appropriate hydrogenation catalyst such as, for example, Raney Nickel 2800 under H 2 at a pressure of, for example, 50 psig
  • an appropriate solvent such as, for example, methanol and ammonia in methanol.
  • a compound in accordance with Formula (I) can be obtained by treating a compound in accordance with Formula (XXXI) with an appropriate acid, such as, for example, TFA or HCl in an appropriate solvent, such as, for example, methylene chloride.
  • an appropriate acid such as, for example, TFA or HCl
  • an appropriate solvent such as, for example, methylene chloride.
  • a compound in accordance with Formula (XXXII) can be obtained by treating an appropriate alkene compound in accordance with Formula (XXV) with an appropriate oxidizing agent, such as, for example, ozone, in an appropriate solvent, such as, for example, DCM.
  • an appropriate oxidizing agent such as, for example, ozone
  • an appropriate solvent such as, for example, DCM.
  • a compound in accordance with Formula (XXXIII) can be obtained by treating a compound in accordance with Formula (XXXII) with an appropriate reducing agent, such as, for example, sodium borohydride in an appropriate solvent, such as, for example, ethanol.
  • an appropriate reducing agent such as, for example, sodium borohydride
  • an appropriate solvent such as, for example, ethanol.
  • a compound in accordance with Formula (I) can be obtained by treating a compound in accordance with Formula (XXXIII) with an appropriate acid, such as, for example, TFA or HCl in an appropriate solvent, such as, for example, methylene chloride.
  • an appropriate acid such as, for example, TFA or HCl
  • an appropriate solvent such as, for example, methylene chloride.
  • a compound in accordance with Formula (XXXIV) can be obtained by treating a compound in accordance with Formula (XXXIII) with an appropriate acylating agent, such as, for example, dimethylcarbamoyl chloride in an appropriate solvent, such as, for example, pyridine.
  • an appropriate acylating agent such as, for example, dimethylcarbamoyl chloride in an appropriate solvent, such as, for example, pyridine.
  • a compound in accordance with Formula (I) can be obtained by treating a compound in accordance with Formula (XXXIV) with an appropriate acid, such as, for example, TFA or HCl in an appropriate solvent, such as, for example, methylene chloride.
  • an appropriate acid such as, for example, TFA or HCl
  • an appropriate solvent such as, for example, methylene chloride.
  • R 12 is as defined above.
  • a compound in accordance with Formula (XXXVI) can be obtained by treating an appropriate amine compound in accordance with Formula (XXXV) with an appropriate acylating agent, such as, for example, trifluoracetic anhydride, in the presence of an appropriate base, such as, for example, diisopropylethylamine, in an appropriate solvent, such as, for example, DCM.
  • an appropriate acylating agent such as, for example, trifluoracetic anhydride
  • a compound in accordance with Formula (Id) can be obtained by treating an appropriate BOC protected amine compound with Formula (XXXVI) with an appropriate acid, such as, for example, trifluoroacetic acid or hydrochloric acid, in an appropriate solvent, such as, for example, DCM or diethyl ether.
  • an appropriate acid such as, for example, trifluoroacetic acid or hydrochloric acid
  • an appropriate solvent such as, for example, DCM or diethyl ether.
  • a compound in accordance with Formula (Ie) can be obtained by treating an appropriate amide compound in accordance with Formula (Id) with an appropriate reducing agent, such as, for example borane THF complex in an appropriate solvent, such as, for example, THF followed after reaction by an appropriate acidic quench, such as, for example, methanol and aqueous hydrochloric acid.
  • an appropriate reducing agent such as, for example borane THF complex in an appropriate solvent, such as, for example, THF
  • an appropriate acidic quench such as, for example, methanol and aqueous hydrochloric acid.
  • a compound in accordance with Formula (XXXVIII) can be obtained by treating an appropriate alcohol compound in accordance with Formula (XXXVII) with an appropriate oxidizing agent, such as, for example, pyridinium chlorochromate, in an appropriate solvent, such as, for example, DCM.
  • an appropriate oxidizing agent such as, for example, pyridinium chlorochromate
  • a compound in accordance with Formula (XXXIX) can be obtained by treating an appropriate aldehyde compound in accordance with Formula (XXXVIII) with any of a set of appropriate primary or secondary amines and an appropriate reducing agent, such as, for example, sodium triacetoxyborohydride in an appropriate solvent, such as, for example, 1,2 dichloroethane.
  • an appropriate reducing agent such as, for example, sodium triacetoxyborohydride
  • an appropriate solvent such as, for example, 1,2 dichloroethane.
  • a compound in accordance with Formula (I) can be obtained by treating an appropriate BOC protected amine compound in accordance with Formula (XXXIX) with an appropriate acid, such as, for example, trifluoroacetic acid or hydrochloric acid, in an appropriate solvent, such as, for example, DCM or diethyl ether.
  • an appropriate acid such as, for example, trifluoroacetic acid or hydrochloric acid
  • an appropriate solvent such as, for example, DCM or diethyl ether.
  • references discussing heterocyclic chemistry include, for example, example, Heterocyclic Chemistry, J.A. Joule, K. Mills, G. F. Smith, 3rd ed., Cheapman and Hall, p. 189-225 (1995); and Heterocyclic Chemistry, TX. Gilchrist, 2 nd ed.
  • MSl Mass Spectrometer Method 1
  • Mobile phase A Water:Acetonitrile:Formic acid (98:2:0.1 v/v)
  • Mobile Phase B Water:Acetonitrile:Formic acid (2:98:0.05 v/v)
  • This instrument can be run in both a 'standard' and 'high resolution mode.' The only difference between the 'standard' and 'high resolution' method is the infusion of reference lock mass ions for the 'high resolution' calibration adjustment. All data reported to 5 decimal places was recorded in 'high resolution' mode.
  • MSlA Mass Spectrometer Method IA
  • Instrumentation Agilent TOF 6210 fronted by an Agilent 1200
  • LC Ionization mode Electrospray Column: Zorbax SB-C8 2. lx30mm x 1.8um
  • Mobile phase A Water:Methanol:Formic acid (98:2:0.1 v/v)
  • Mobile Phase B Water:Methanol:Formic acid (2:98:0.05 v/v) Gradient: Time in min (%B): 0(5); 1.5(95); 1.9(95); 2(5).
  • This instrument can be run in both a 'standard' and 'high resolution mode.' The only difference between the 'standard' and 'high resolution' method is the infusion of reference lock mass ions for the 'high resolution' calibration adjustment. All data reported to 5 decimal places was recorded in 'high resolution' mode.
  • MS2 Mass Spectrometer Method 2
  • Electrospray Column Acquity UPLC BEH C 18 2. lx50mm x 1.7um
  • multiplicities of the NMR spectra absorptions may be abbreviated by: s, singlet; br, broad peak; bs, broad singlet; d, doublet; t, triplet; q, quartet; dd, doublet of doublets; dt, doublet of triplets; m, multiplet.
  • Method A Separation using reverse-phase HPLC with gradient elution on a Phenomenex Gemini Cl 8 column (250 x 21.2 mm, 5 micron) as stationary phase and ACN in H 2 O (+ 0.1% formic acid) as the mobile phase.
  • Method B Elution on silica gel using an isocratic run with either pure organic solvent (such as: CH 2 CL 2 , EtOAc, ether, etc.) or mixtures of solvents (such as 25% CH 2 Cl 2 in Hexane, 10% MeOH in CH 2 Cl 2 , etc.).
  • Method C Elution on silica gel using an increasing gradient of polar solvent (such as: MeOH (0-10%) in EtOAc, CH 2 Cl 2 (0-50%) in hexane, EtOAc (0-40%) in hexane, etc.).
  • Method E Preparative separation using a Berger SFC equipped with a Chiral Tech IC column (21 x 250 mm) with dual wavelength detector (220 & 254 nm) and 25% MeOH with 0.5% dimethyl ethylamine in CO 2 as eluant. Flow rate was 50-70 ml/min. Purity of collected fractions were determined using an analytical SFC system equipped with diode array and mass spec detector.
  • Product IB (S)-tert-butyl 3-(3,4-dichlorophenyl)-3-(2- (dimethylcarbamoyloxy)ethyl)piperidine-l-carboxylate.
  • Product 2A (S)-tert-butyl 3-(3,4-dichlorophenyl)-3-(2- (methylcarbamoyloxy)ethyl)piperidine-l-carboxylate.
  • Product 3A 2-(3-chloro-4-fluorophenyl)acetonitrile.
  • the mixture was stirred for an additional 3 hr at 25°C, and then the reaction was heated to 45°C for an additional 2 hr.
  • the reaction was cooled, separated into layers and the organic layer washed with 0.5 N NaOH then brine.
  • the chloroform layer was dried over Na 2 SO 4 , filtered, and concentrated.
  • the aqueous layers were combined and treated with IN NaOH solution and bleach (caution exothermic) before disposal of the cyanide containing waste.
  • the pure 3A (22.05 g, 97%) was obtained as an oil.
  • the reaction was resubmitted to the Parr shaker (50 psi H2) for an additional 18 hr at 55°C.
  • the reaction was filtered through Celite ® and the filter cake was washed with EtOH.
  • the EtOH was removed on a rotary evaporator and the residue was extracted with EtOAC and NaHCO 3 solution.
  • the organic layer was dried over Na 2 SO 4 , filtered, and concentrated. There was 5.1 g of crude material at this point.
  • the residue was then purified by silica gel chromatography using as eluent a gradient of from 1 : 1 EtOAc/DCM to 1 : 1 EtOAC/DCM + 10% MeOH.
  • Example 3 compound (2.5 g, 9.70 mmol) was purified by Prep LC using the Gemini NX column with eluent pH 9.0 (Chromatographic method D) to remove the des chloro impurity.
  • the SFC analysis of the purified final solid shows that this material was obtained in >98% ee.
  • Example 3 compound (2.5 g, 9.70 mmol) was purified by Prep LC using the Gemini NX column with eluent pH 9.0 (Chromatographic method D) to remove the des chloro impurity.
  • Product 6B (S)-methyl 2-(3-(3,4-dichlorophenyl)piperidin-3-yl)acetate.
  • (S)-2-(3-(4-chlorophenyl)piperidin-3-yl)ethanol also can be prepared in a manner analogous to that reported for the dichloro derivative in Example 31 below using the method generally described in Patent No. EP591040B1. It is further contemplated that the enantiomers in that method can be separated by fractional crystallization of diastereomeric salts or preparative chiral stationary phase supercritical fluid chromatography (CSP SFC). [270] Example 8. (S)-2-(3-(3-chlorophenyl)piperidin-3-yl)ethanol.
  • Product 9B (S)-tert-butyl 3-(2-azidoethyl)-3-(3,4- dichlorophenyl)piperidine-l-carboxylate.
  • Product 9C (S)-tert-butyl 3-(2-aminoethyl)-3-(3,4- dichlorophenyl)piperidine-l-carboxylate.
  • Product 1OA (S)-tert-butyl 3-(3,4-dichlorophenyl)-3-(2-(2,2,2- trifluoroacetamido)ethyl)piperidine-l-carboxylate.
  • Flash silica gel chromatography gave three pure products as foamy solids. Typical product distribution for sulfoxide formation after flash silica gel chromatography was sulfoxide (major component 50-75%), sulfone (minor product 15-30%) and small amount of sulfide (5-10%). Typical product distribution for sulfone formation was > 90%.
  • Table 2 shows various compounds that were prepared by the general route illustrated in Examples 1-9. Table 2 also provides the intermediate from Table 1 that was used to prepare each compound. Yields in the reactions varied from approximately 20-80%.
  • Product 24A (S)-tert-butyl 3-(3,4-dichlorophenyl)-3-vinylpiperidine-l- carboxylate.
  • the crude 24B (1.71 g, 4.77 mmol) was dissolved in EtOH (75 mL) and then cooled to 0 0 C on an ice bath. When the solution had reached temperature, solid NaBH 4 (0.181 g, 4.77 mmol) was added and the solution stirred for 30 min. The reaction was quenched with 0.5 rnL of acetone, and allowed to warm to room temperature. Most of the EtOH was removed on the rotary evaporator. The product was redissolved in EtOAc and partitioned between EtOAc and NaHC ⁇ 3 solution. The organic layer was dried over Na 2 SO 4 , filtered and concentrated yielding a white solid.
  • Product 24D (S)-tert-butyl 3-(3,4-dichlorophenyl)-3- ((dimethylcarbamoyloxy)methyl)piperidine-l-carboxylate.
  • Table 3 shows various compounds that were prepared by the general route illustrated in Examples 1-9 and 24. Table 3 also provides the intermediate from Table 1 that was used to prepare each compound.
  • Product 32B (S)-tert-butyl 3-(2-(2-cyanoethylamino)ethyl)-3-(3,4- dichlorophenyl)piperidine-l-carboxylate.
  • At least one compound of Formula (I), including the compounds described in the Examples hereof, when tested in at least one in vitro assay described below is active towards norepinephrine transport receptors and/or dopamine transport receptors.
  • at least one compound of the invention is an effective norepinephrine transport receptor and/or dopamine transport receptor ligand.
  • the in vitro activity may be related to in vivo activity but may not be linearly correlated with binding affinity.
  • a compound can be tested for its activity toward norepinphrine transport receptors and dopamine transport receptors, and Ki values can be obtained to determine the activity for a particular compound towards both of these receptors.
  • At least one compound in accordance with Formula (I) is diluted 1 :20 in buffer and incubated with the cells for 30 min prior to adding dye.
  • plates are read after a 20 min (NET or DAT) dye incubation to determine percent effect with respect to total signal (0.5% DMSO, final) and background signal (NET: lO ⁇ M desipramine, DAT: lO ⁇ M GBR12909).
  • NET lO ⁇ M desipramine
  • DAT lO ⁇ M GBR12909
  • At least one compound in accordance with Formula (I) has a Ki value of less than about 1.5 ⁇ M at NET and DAT.
  • at least one compound of Formula (I) showed activity in the above referenced assay as essentially described above via a Ki value of between about 0.1 nM to about 1.5 ⁇ M.
  • at least one compound of Formula (I) showed activity in the above referenced assay as essentially described above via a Ki value of between about 0.1 nM to about 700 nM.
  • at least one compound of Formula (I) showed activity in the above referenced assay as essentially described above via a Ki value of between about 0.1 nM and 200 nM.
  • At least one compound of Formula (I) showed activity in the above referenced assay as essentially described above via a Ki value of between about 0.1 nM and 100 nM. In one embodiment, at least one compound of Formula (I) showed activity in the above referenced assay as essentially described above via a Ki value of less than about 1200 nM. In another embodiment, at least one compound of Formula (I) showed activity in the above referenced assay as essentially described above via a Ki value of less than about 100 nM. In yet another embodiment, at least one compound of Formula (I) showed activity in the above referenced assay as essentially described above via a Ki value of less than about 50 nM.
  • a compound of Formula (I) showed activity in the above referenced assay as essentially described above via a Ki value of less than about 10 nM.
  • C m _C n means that the modified group contains from m to n carbon atoms.
  • Ci.C ⁇ -alkyl means an alkyl group containing from
  • hydrocarbon refers to a chemical structure comprising only carbon and hydrogen atoms.
  • alkyl means a straight or branched chain alkane (hydrocarbon) radical. In some embodiments, the alkyl comprises from 1 to 12 carbon atoms. In some embodiments, the alkyl comprises from 1 to 6 carbon atoms. And in some embodiments, the alkyl comprises from 1 to 3 carbon atoms.
  • alkyl groups include, for example, methyl; ethyl; propyl; isopropyl; 1-methylpropyl; 2-methylpropyl; n-butyl, t-butyl; isobutyl; 3-methylbutyl; pentyl; hexyl; isohexyl; heptyl; 4,4-dimethylpentyl; diethylpentyl; octyl; 2,2,4-trimethylpentyl; nonyl; decyl; undecyl; and dodecyl.
  • cycloalkyl refers to a fully saturated cyclic hydrocarbon group.
  • the cycloalkyl may comprise one or more rings. In some embodiments, the cycloalkyl comprises a single ring. In some embodiments, the cycloalkyl comprises from 3 to 10 carbons. In other embodiments, the cycloalkyl comprises from 3 to 6 carbons. Examples of cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • heterocycloalkyl refers to a saturated or partially unsaturated hydrocarbon ring in which at least one ring carbon (and any associated hydrogen atoms) are independently replaced with at least one atom(s) selected from O, N, NH, and S. In some embodiments, the at least one ring carbon (and any associated hydrogen atoms) is replaced with an atom(s) selected from O, N, and NH. In some embodiments, the at least one ring carbon (and any associated hydrogen atoms) is replaced with an atom selected from O and N. In some embodiments, at least two carbon atoms (and any associated hydrogen atoms) are replaced with atoms independently selected from O, N, NH, and S. In some embodiments, at least two carbon atoms (and any associated hydrogen atoms) are replaced with atoms independently selected from O, N, and S.
  • aryl refers to an aromatic (i.e., fully unsaturated) hydrocarbon ring structure.
  • the aryl comprises one ring (i.e., the aryl is phenyl).
  • halogen and "halo" means chlorine, bromine, fluorine, or iodine.
  • the halogen atoms in a molecule are selected from the group consisting of chlorine or fluorine.
  • the halogen atoms in a molecule are chlorine.
  • the halogen atoms in a molecule are fluorine.
  • haloalkyl refers to an alkyl bonded to a single halogen or multiple halogens.
  • haloalkyls include -CHCl 2 , -CHF 2 , and -CF 3 .
  • alkoxy means -O-alkyl. Examples of alkoxys include methoxy, ethoxy, propoxy, and butoxy.
  • a pharmaceutically acceptable moiety e.g., a salt, dosage form, carrier, diluent, or excipient
  • a pharmaceutically acceptable moiety has one or more benefits that outweigh any deleterious effect that the moiety may have. Deleterious effects may include, for example, excessive toxicity, irritation, allergic response, and other problems and complications.
  • ACN means acetonitrile
  • BH 3 .THF means borane tetrahydrofuran.
  • CH 2 Cl 2 means dichloromethane.
  • CH 3 SO 2 Cl means methanesulfonyl chloride.
  • CO 2 means carbon dioxide
  • DAT dopamine transport receptor
  • DCM dichloromethane
  • DIPEA N,N-diisopropylethylamine
  • DMF N,N-dimethylformamide
  • DMSO dimethyl sulfoxide
  • DMSO-d6 means deuterated dimethyl sulfoxide.
  • EDC means l-ethyl-3-(3-dimethylaminopropyl) carbodiimide.
  • ee means enantiomeric excess.
  • Et 3 N means triethylamine
  • EtOAc means ethyl acetate.
  • EtOH means ethanol.
  • HCl means hydrochloric acid
  • HPLC high performance liquid chromatography
  • K 2 CO 3 means potasssium carbonate.
  • LAH Lithium aluminum hydride
  • LCMS liquid chromatography mass spectral detection
  • LDA lithium diisopropyl amide
  • m-CPBA meta-chloroperbenzoic acid
  • MgSO 4 means magnesium sulfate.
  • min means minute or minutes.
  • MS means mass spectrum.
  • N 2 means nitrogen gas
  • NaBH 4 sodium borohydride
  • NaH sodium hydride
  • NaHCO 3 means sodium bicarbonate.
  • NaOH means sodium hydroxide.
  • Na 2 SO 4 means sodium sulfate
  • NET norepinephrine transport receptor
  • NH 4 Cl means ammonium chloride
  • NMR nuclear magnetic resonance
  • PCC pyridinium chlorochromate
  • PDC pyridinium dichromate
  • r t means retention time
  • SFC means supercritical fluid chromatography.
  • TBTU means O-(benzotriazol-l-yl)-N,N,N',N'- tetramethy luronium tetrafluoroborate .
  • TFA means trifluoroacetic acid
  • THF tetrahydrofuran
  • UV ultraviolet

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  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Biomedical Technology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Neurology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Psychiatry (AREA)
  • Addiction (AREA)
  • Pain & Pain Management (AREA)
  • Hydrogenated Pyridines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Pyridine Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Cette invention concerne d'une manière générale des composés pipéridines quaternaires, en particulier des composés 3-phénylpipéridines substituées et leurs sels. Cette invention concerne également des compositions pharmaceutiques comprenant un tel composé, des utilisations d'un tel composé (comprenant, par exemple, des procédés de traitement et des préparations médicamenteuses), et des procédés de fabrication d'un tel composé.
PCT/SE2009/051427 2008-12-16 2009-12-15 Dérivés quaternaires de pipéridine et leurs utilisations WO2010071575A1 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US12291208P 2008-12-16 2008-12-16
US61/122,912 2008-12-16
US22638909P 2009-07-17 2009-07-17
US61/226,389 2009-07-17
US22907309P 2009-07-28 2009-07-28
US61/229,073 2009-07-28

Publications (1)

Publication Number Publication Date
WO2010071575A1 true WO2010071575A1 (fr) 2010-06-24

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AR (1) AR074755A1 (fr)
TW (1) TW201026666A (fr)
UY (1) UY32333A (fr)
WO (1) WO2010071575A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011075470A1 (fr) * 2009-12-15 2011-06-23 Astrazeneca Pharmaceuticals Lp Composés pipéridines quaternaires et leurs utilisations
CN105017244A (zh) * 2014-04-16 2015-11-04 上海药明康德新药开发有限公司 顺反叔丁基-4-氧六氢化-1H-吡咯[3,4-c]吡啶-2(3H)-羧酸叔丁酯的合成方法
CN116462607A (zh) * 2023-02-06 2023-07-21 中山大学 一种氰基化合物及其制备方法和应用

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0679642A1 (fr) * 1994-04-28 1995-11-02 Takeda Chemical Industries, Ltd. Dérivés hétérocycliques condensés, leur préparation et utilisation
WO1997025322A1 (fr) * 1996-01-05 1997-07-17 Pfizer Research And Development Company, N.V./S.A. 3-azetidinylalkylpiperidines ou -pyrrolidines en tant qu'antagonistes des tachykinines
WO1997027185A1 (fr) * 1996-01-22 1997-07-31 Pfizer Research And Development Company, N.V./S.A. Piperidones, antagonistes de la tachykinine
WO2005121092A1 (fr) * 2004-06-08 2005-12-22 A. Carlsson Research Ab Nouvelles piperidines substituees utilisees comme modulateurs de la neurotransmission de la dopamine
WO2008148801A2 (fr) * 2007-06-05 2008-12-11 Nsab, Filial Of Neurosearch Sweden Ab, Sverige Nouvelles phénylpyrrolidines disubstituées en tant que modulateurs de la neurotransmission catécholaminergique corticale

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0679642A1 (fr) * 1994-04-28 1995-11-02 Takeda Chemical Industries, Ltd. Dérivés hétérocycliques condensés, leur préparation et utilisation
WO1997025322A1 (fr) * 1996-01-05 1997-07-17 Pfizer Research And Development Company, N.V./S.A. 3-azetidinylalkylpiperidines ou -pyrrolidines en tant qu'antagonistes des tachykinines
WO1997027185A1 (fr) * 1996-01-22 1997-07-31 Pfizer Research And Development Company, N.V./S.A. Piperidones, antagonistes de la tachykinine
WO2005121092A1 (fr) * 2004-06-08 2005-12-22 A. Carlsson Research Ab Nouvelles piperidines substituees utilisees comme modulateurs de la neurotransmission de la dopamine
WO2008148801A2 (fr) * 2007-06-05 2008-12-11 Nsab, Filial Of Neurosearch Sweden Ab, Sverige Nouvelles phénylpyrrolidines disubstituées en tant que modulateurs de la neurotransmission catécholaminergique corticale

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011075470A1 (fr) * 2009-12-15 2011-06-23 Astrazeneca Pharmaceuticals Lp Composés pipéridines quaternaires et leurs utilisations
CN105017244A (zh) * 2014-04-16 2015-11-04 上海药明康德新药开发有限公司 顺反叔丁基-4-氧六氢化-1H-吡咯[3,4-c]吡啶-2(3H)-羧酸叔丁酯的合成方法
CN116462607A (zh) * 2023-02-06 2023-07-21 中山大学 一种氰基化合物及其制备方法和应用
CN116462607B (zh) * 2023-02-06 2024-09-03 中山大学 一种氰基化合物及其制备方法和应用

Also Published As

Publication number Publication date
UY32333A (es) 2010-07-30
AR074755A1 (es) 2011-02-09
TW201026666A (en) 2010-07-16

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