WO2009058120A1 - Modulateurs des récepteurs nicotiniques de l'acétylcholine - Google Patents

Modulateurs des récepteurs nicotiniques de l'acétylcholine Download PDF

Info

Publication number
WO2009058120A1
WO2009058120A1 PCT/US2007/023152 US2007023152W WO2009058120A1 WO 2009058120 A1 WO2009058120 A1 WO 2009058120A1 US 2007023152 W US2007023152 W US 2007023152W WO 2009058120 A1 WO2009058120 A1 WO 2009058120A1
Authority
WO
WIPO (PCT)
Prior art keywords
substituted
hydrocarbyl
compound
heteroatom
ring
Prior art date
Application number
PCT/US2007/023152
Other languages
English (en)
Inventor
Faming Jiang
Taline Khroyan
Cris M. Olsen
Willma E. Polgar
Lawrence R. Toll
Nurulain T. Zaveri
Original Assignee
Sri International
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sri International filed Critical Sri International
Priority to PCT/US2007/023152 priority Critical patent/WO2009058120A1/fr
Publication of WO2009058120A1 publication Critical patent/WO2009058120A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • 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
    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems

Definitions

  • This disclosure relates generally to compounds that modulate human neuronal nicotinic acetylcholine receptors, and more particularly relates to compounds useful in the treatment of conditions that are mediated by such receptors.
  • Nicotine the active ingredient in tobacco, stimulates neuronal receptors by triggering the release of neurotransmitters such as dopamine and acetylcholine. To produce this effect, nicotine is believed to bind to one or more of a family of receptors known as nicotinic acetylcholine receptors (nAChRs).
  • nAChRs nicotinic acetylcholine receptors
  • NRT nicotine replacement therapy
  • Non-nicotine based methods of aiding smoking cessation include the use of anti-depressants and weight-reducing medications.
  • Coe et al., (2005) J. Med. Chem. 48, 3474 describes the synthesis of an azepine derivative that, like nicotine, binds to one of the nAChRs. It is hypothesized that a therapeutic agent that competitively binds to nAChRs, precluding the binding of nicotine, would thereby limit or eliminate the satisfaction that smoking provides.
  • -octane derivatives which are useful for the treatment of a range of diseases or conditions or disorders characterized by decreased cholinergic function or responsive to the activity of nicotinic ACh receptor modulators.
  • U.S. Pat. No. 6,541 ,478 describes a method for treating a person for nicotine dependency by administering an opioid antagonist such as naltrexone.
  • U.S. Pat. No. 6,495,605 describes methods and compositions that utilize the optically pure (+)-isomer of bupropion to assist in smoking cessation, and for treating smoking and nicotine addiction.
  • nAChRs have been identified as targets for drugs that aid in smoking cessation.
  • 6,894,042, 6,858,613, 6,852,716, and 6,849620 are directed towards azabicyclic compounds that are useful in pharmaceuticals in which the ⁇ 7 nAChR is known to be involved.
  • nAChRs play an important role in regulating CNS and other physiological functions by mediating the endogenous neurotransmitter, acetylcholine.
  • nAChRs are associated with medical conditions such as learning disorders, eating disorders, Alzheimer's disease and other memory-impairing conditions,
  • Parkinsons disease and addictions to drugs such as opiates and cocaine.
  • drugs such as opiates and cocaine.
  • nicotine addiction there remains a need in the art for improved therapeutic approaches to these nAChR-associated conditions..
  • nAChRs (such as nicotine) or other medical conditions involving nAChRs might involve a compound that: (1 ) has a selective and high binding affinity for one or more subtype of neuronal nAChR; (2) has a low binding affinity for muscular AChRs; (3) has low toxicity in vivo; and (4) can be administered to the patient effectively and via one or more of a variety of methods.
  • the present disclosure provides a method for modulating a nicotinic acetylcholine receptor (nAChR).
  • the method comprises administering to a patient a therapeutically effective amount of a compound comprising a 7- to 1 1-membered azabicyclo ring attached to a bulk-providing moiety.
  • the bulk-providing moiety is selected from: (i) N-heteroaryl; (ii) indolinyl-2-one; and (iii) N-substituted aryl.
  • the disclosure provides a method for treating a patient suffering from a chemical addition.
  • the method comprises administering to the patient a therapeutically effective amount of a compound capable of binding to a nicotinic acetylcholine receptor.
  • the compound comprises a 7- to 1 1 -membered azabicyclo ring attached to a bulk-providing moiety selected from: (i) N-heteroaryl; (ii) indolinyl-2-one; and (iii) N-substituted aryl.
  • the disclosure provides a compound comprising a 7- to 1 1 -membered azabicyclo ring that has a bulk-providing moiety.
  • the bulk-providing moiety is selected from: (i) N-heteroaryl; (ii) indolinyl-2-one; and (iii) N-substituted aryl, and the compound is a ligand for a nicotinic acetylcholine receptor (nAChR).
  • nAChR nicotinic acetylcholine receptor
  • the disclosure provides a composition comprising:
  • a compound comprising a 7- to 1 1 -membered azabicyclo ring that has a bulk-providing moiety selected from: (i) N-heteroaryl; (ii) indolinyl-2-one; and (iii) N-substituted aryl; and
  • the compound is a ligand for a nicotinic acetylcholine receptor (nAChR).
  • nAChR nicotinic acetylcholine receptor
  • an active agent includes not only a single active agent but also a combination or mixture of two or more different active agents
  • reference to "a polymer” includes a single polymer as well as two or more polymers in combination or admixture, and the like.
  • the terms “may,” “optional,” “optionally,” or “may optionally” mean that the subsequently described circumstance may or may not occur, so that the description includes instances where the circumstance occurs and instances where it does not.
  • the phrase “optionally substituted” means that a non-hydrogen substituent may or may not be present on a given atom, and, thus, the description includes structures wherein a non-hydrogen substituent is present and structures wherein a non- hydrogen substituent is not present.
  • alkyl refers to a branched or unbranched saturated hydrocarbon group typically although not necessarily containing 1 to about 24 carbon atoms, such as methyl, ethyl, rc-propyl, isopropyl, H-butyl, isobutyl, ?-butyl, octyl, decyl, and the like, as well as cycloalkyl groups such as cyclopentyl, cyclohexyl and the like.
  • alkyl groups herein may contain 1 to about 18 carbon atoms, and such groups may contain 1 to about 12 carbon atoms.
  • lower alkyl intends an alkyl group of 1 to 6 carbon atoms.
  • Substituted alkyl refers to alkyl substituted with one or more substituent groups
  • heteroatom-containing alkyl and “heteroalkyl” refer to an alkyl substituent in which at least one carbon atom is replaced with a heteroatom, as described in further detail infra.
  • alkyl and “lower alkyl” include linear, branched, cyclic, unsubstituted, substituted, and/or heteroatom-containing alkyl or lower alkyl, respectively.
  • alkenyl refers to a linear, branched or cyclic hydrocarbon group of 2 to about 24 carbon atoms containing at least one double bond, such as ethenyl, w-propenyl, isopropenyl, «-butenyl, isobutenyl, octenyl, decenyl, tetradecenyl, hexadecenyl, eicosenyl, tetracosenyl, and the like.
  • alkenyl groups herein may contain 2 to about 18 carbon atoms, and for example may contain 2 to 12 carbon atoms.
  • lower alkenyl intends an alkenyl group of 2 to 6 carbon atoms.
  • substituted alkenyl refers to alkenyl substituted with one or more substituent groups
  • heteroatom-containing alkenyl and “heteroalkenyl” refer to alkenyl in which at least one carbon atom is replaced with a heteroatom.
  • alkenyl and “lower alkenyl” include linear, branched, cyclic, unsubstituted, substituted, and/or heteroatom-containing alkenyl and lower alkenyl, respectively.
  • alkynyl refers to a linear or branched hydrocarbon group of 2 to 24 carbon atoms containing at least one triple bond, such as ethynyl, n- propynyl, and the like. Generally, although again not necessarily, alkynyl groups herein may contain 2 to about 18 carbon atoms, and such groups may further contain 2 to 12 carbon atoms. The term “lower alkynyl” intends an alkynyl group of 2 to 6 carbon atoms.
  • substituted alkynyl refers to alkynyl substituted with one or more substituent groups
  • heteroatom-containing alkynyl and “heteroalkynyl” refer to alkynyl in which at least one carbon atom is replaced with a heteroatom.
  • alkynyl and “lower alkynyl” include linear, branched, unsubstituted, substituted, and/or heteroatom-containing alkynyl and lower alkynyl, respectively.
  • alkoxy intends an alkyl group bound through a single, terminal ether linkage; that is, an "alkoxy” group may be represented as -O-alkyl where alkyl is as defined above.
  • a "lower alkoxy” group intends an alkoxy group containing 1 to 6 carbon atoms, and includes, for example, methoxy, ethoxy, ⁇ -propoxy, isopropoxy, t- butyloxy, etc.
  • Substituents identified as "Ci-C 6 alkoxy” or “lower alkoxy” herein may, for example, may contain 1 to 3 carbon atoms, and as a further example, such substituents may contain 1 or 2 carbon atoms (i.e., methoxy and ethoxy).
  • aryl refers to an aromatic substituent generally, although not necessarily, containing 5 to 30 carbon atoms and containing a single aromatic ring or multiple aromatic rings that are fused together, directly linked, or indirectly linked (such that the different aromatic rings are bound to a common group such as a methylene or ethylene moiety).
  • Aryl groups may, for example, contain 5 to 20 carbon atoms, and as a further example, aryl groups may contain 5 to 12 carbon atoms.
  • aryl groups may contain one aromatic ring or two fused or linked aromatic rings, e.g., phenyl, naphthyl, biphenyl, diphenylether, diphenylamine, benzophenone, and the like.
  • “Substituted aryl” refers to an aryl moiety substituted with one or more substituent groups
  • heteroatom-containing aryl and “heteroaryl” refer to aryl substituent, in which at least one carbon atom is replaced with a heteroatom, as will be described in further detail infra. If not otherwise indicated, the term “aryl” includes unsubstituted, substituted, and/or heteroatom-containing aromatic substituents.
  • aralkyl refers to an alkyl group with an aryl substituent
  • alkaryl refers to an aryl group with an alkyl substituent, wherein “alkyl” and “aryl” are as defined above.
  • aralkyl and alkaryl groups herein contain 6 to 30 carbon atoms.
  • Aralkyl and alkaryl groups may, for example, contain 6 to 20 carbon atoms, and as a further example, such groups may contain 6 to 12 carbon atoms.
  • amino is used herein to refer to the group -NZ 1 Z 2 wherein Z 1 and Z 2 are hydrogen or nonhydrogen substituents, with nonhydrogen substituents including, for example, alkyl, aryl, alkenyl, aralkyl, and substituted and/or heteroatom-containing variants thereof.
  • halo and “halogen” are used in the conventional sense to refer to a chloro, bromo, fluoro or iodo substituent.
  • heteroatom-containing as in a "heteroatom-containing alkyl group” (also termed a “heteroalkyl” group) or a “heteroatom-containing aryl group” (also termed a “heteroaryl” group) refers to a molecule, linkage or substituent in which one or more carbon atoms are replaced with an atom other than carbon, e.g., nitrogen, oxygen, sulfur, phosphorus or silicon, typically nitrogen, oxygen or sulfur.
  • heteroalkyl refers to an alkyl substituent that is heteroatom-containing
  • heterocyclic refers to a cyclic substituent that is heteroatom-containing
  • heteroalkyl groups include alkoxyaryl, alkylsulfanyl-substituted alkyl, N-alkylated amino alkyl, and the like.
  • heteroaryl substituents include pyrrolyl, pyrrolidinyl, pyridinyl, quinolinyl, indolyl, furyl, pyrimidinyl, imidazolyl, 1 ,2,4-triazolyl, tetrazolyl, etc.
  • heteroatom- containing alicyclic groups are pyrrolidino, morpholino, piperazino, piperidino, tetrahydrofuranyl, etc.
  • Hydrocarbyl refers to univalent hydrocarbyl radicals containing 1 to about 30 carbon atoms, including 1 to about 24 carbon atoms, further including 1 to about 18 carbon atoms, and further including about 1 to 12 carbon atoms, including linear, branched, cyclic, saturated and unsaturated species, such as alkyl groups, alkenyl groups, aryl groups, and the like.
  • Substituted hydrocarbyl refers to hydrocarbyl substituted with one or more substituent groups
  • heteroatom-containing hydrocarbyl refers to hydrocarbyl in which at least one carbon atom is replaced with a heteroatom. Unless otherwise indicated, the term “hydrocarbyl” is to be interpreted as including substituted and/or heteroatom-containing hydrocarbyl moieties.
  • substituted as in “substituted hydrocarbyl,” “substituted alkyl,” “substituted aryl,” and the like, as alluded to in some of the aforementioned definitions, is meant that in the hydrocarbyl, alkyl, aryl, or other moiety, at least one hydrogen atom bound to a carbon (or other) atom is replaced with one or more non-hydrogen substituents.
  • substituents include, without limitation: functional groups such as halo, hydroxyl, sulfhydryl, Ci-C 24 alkoxy, C 2 -C 24 alkenyloxy, C 2 -C 24 alkynyloxy, C 5 -C 20 aryloxy, acyl (including C 2 -C 24 alkylcarbonyl (-CO-alkyl) and C 6 -C 20 arylcarbonyl (-CO-aryl)), acyloxy (- O-acyl), C 2 -C 24 alkoxycarbonyl (-(CO)-O-alkyl), C 6 -C 20 aryloxycarbonyl (-(CO)-O-aryl), halocarbonyl (-CO)-X where X is halo), C 2 -C 24 alkylcarbonato (-O-(CO)-O-alkyl), C 6 -C 20 arylcarbonato (-O-(CO)-O-aryl), carboxy (--C
  • the aforementioned functional groups may, if a particular group permits, be further substituted with one or more additional functional groups or with one or more hydrocarbyl moieties such as those specifically enumerated above.
  • the above-mentioned hydrocarbyl moieties may be further substituted with one or more functional groups or additional hydrocarbyl moieties such as those specifically enumerated.
  • reference to H is meant to include 1 H, 2 H (i.e., D) and 3 H (i.e., T), and reference to C is meant to include 12 C and all isotopes of carbon (such as 13 C).
  • the terms “treating” and “treatment” as used herein refer to reduction in severity and/or frequency of symptoms, elimination of symptoms and/or underlying cause, prevention of the occurrence of symptoms and/or their underlying cause, and improvement or remediation of damage.
  • Preventing" a disorder or unwanted physiological event in a patient refers specifically to the prevention of the occurrence of symptoms and/or their underlying cause, wherein the patient may or may not exhibit heightened susceptibility to the disorder or event.
  • an effective amount of a therapeutic agent is meant a nontoxic but sufficient amount of a beneficial agent to provide the desired effect.
  • the amount of beneficial agent that is “effective” will vary from subject to subject, depending on the age and general condition of the individual, the particular beneficial agent or agents, and the like. Thus, it is not always possible to specify an exact “effective amount.” However, an appropriate “effective” amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation.
  • an "effective amount" of a beneficial refers to an amount covering both therapeutically effective amounts and prophylactically effective amounts.
  • a "therapeutically effective amount” of an active agent refers to an amount that is effective to achieve a desired therapeutic result
  • a “prophylactically effective amount” of an active agent refers to an amount that is effective to prevent an unwanted physiological condition.
  • Therapeutically effective and prophylactically effective amounts of a given active agent will typically vary with respect to factors such as the type and severity of the disorder or disease being treated and the age, gender, and weight of the patient.
  • a “pharmaceutically acceptable” component is meant a component that is not biologically or otherwise undesirable, i.e., the component may be incorporated into a pharmaceutical formulation of the disclosure and administered to a patient as described herein without causing any significant undesirable biological effects or interacting in a deleterious manner with any of the other components of the formulation in which it is contained.
  • pharmaceutically acceptable refers to an excipient, it is generally implied that the component has met the required standards of toxicological and manufacturing testing or that it is included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug Administration.
  • pharmacologically active refers to a derivative or analog (e.g., a salt, ester, amide, conjugate, metabolite, isomer, fragment, etc.) having the same type of pharmacological activity as the parent compound and approximately equivalent in degree.
  • controlled release refers to a formulation, dosage form, or region thereof from which release of a beneficial agent is not immediate, i.e., with a "controlled release” dosage form, administration does not result in immediate release of the beneficial agent in an absorption pool.
  • controlled release includes sustained release and delayed release formulations.
  • sustained release (synonymous with “extended release”) is used in its conventional sense to refer to a formulation, dosage form, or region thereof that provides for gradual release of a beneficial agent over an extended period of time, and that preferably, although not necessarily, results in substantially constant blood levels of the agent over an extended time period.
  • naturally occurring refers to a compound or composition that occurs in nature, regardless of whether the compound or composition has been isolated from a natural source or chemically synthesized.
  • binding refers to the formation of a complex involving a receptor and a ligand
  • binding affinity refers to a compound's capacity to bind to a receptor. Binding affinity may be quantified, for example, by Kj. 100050)
  • a compound may exhibit "selective" binding, by which is meant that the compound's affinity for binding to one or more particular receptor(s) is greater than the compound's affinity for binding to one other receptor, multiple other receptor, or all other receptors. For a compound that exhibits selective binding, therefore, the binding constant Kj for the compound binding with one receptor is lower than the Ki for the compound binding with one or more other receptor(s).
  • a compound that is selective for receptor "A” over receptor “B” will have a binding constant ratio Kj(A)/Kj(B) that is less than 1/1.
  • 000511 the disclosure provides compounds comprising a 7-, 8-, 9-, 10- or 1 1 -membered azabicyclo ring.
  • the azabicyclo ring may have any configuration, such as [2.2.1 ], [2.2.2], [3.2.1 ], [3.3.1 ], [3.2.2], [3.3.2], or [3.3.3], with a nitrogen atom located at any position.
  • the azabicylco ring may be substituted or unsubstituted at any position.
  • the azabicyclo ring may be unsaturated.
  • azabicyclo rings include various isomers of azabicyclo[2.2.1 ]heptanyl, azabicylco[3.2.1 ]octanyl, azabicylco[2.2.2]octanyl, azabicylco[3.2.2]nonanyl, azabicylco[3.3.1 ]nonanyl, azabicylco[3.3.2]decanyl, and azabicyclo[3.3.3]undecanyl rings, any of which may be saturated or unsaturated.
  • Example formulae of azabicyclo ring configurations, showing only the ring atoms, are as follows:
  • R 1 is selected from H, hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, and substituted heteroatom-containing hydrocarbyl.
  • R 1 groups include substituted or unsubstituted Ci-C 20 alkylene, C 2 -C 20 alkenylene, C 2 -C 20 alkynylene, C 5 -C 24 arylene, C 6 -C 24 alkarylene, or C 6 -C 24 aralkylene.
  • R 1 examples include methyl, ethyl, benzyl, -C(O)H-, -C(O)-O-CH 3 , -C(O)-O-CH 2 CH 3 , and -C(O)-O-C(CH 3 ) 3 .
  • the compounds of the disclosure further comprise a bulk-providing moiety, and an optional linking moiety.
  • the compounds have the structure of formula (I)
  • N j represents the azabicyclo ring
  • m is an integer selected from 0 or 1
  • L is a linking moiety
  • R 1 is selected from H, hydrocarbyl, substituted hydrocarbyl, heteroatom- containing hydrocarbyl, substituted heteroatom-containing hydrocarbyl, and nitrogen protecting groups; and [00058] R 2 is a bulk-providing moiety.
  • R 1 is selected from H, substituted and unsubstituted Ci-C 24 alkyl, substituted and unsubstituted Ci-C 24 heteroalkyl, substituted and unsubstituted C 5 -C 24 aryl, substituted and unsubstituted C 5 -C 24 heteroaryl, and nitrogen protecting groups
  • R 2 is selected from substituted and unsubstituted C 5 -C 24 aryl, and substituted and unsubstituted C 5 -C 24 heteroaryl.
  • R and R are selected from H, substituted or unsubstituted C
  • the compounds have the structure of formulae (IA), (IB), or (IC)
  • n is an integer selected from 0 or 1 ;
  • ⁇ and ⁇ are optional double bonds, provided that either ⁇ or ⁇ is present; and
  • m, L, R 1 , and R 2 are as defined for formula (I).
  • the nitrogen atom of the azabicyclo compound forms a one- atom bridge.
  • Preferred azabicyclo compounds having nitrogen as a one-atom bridge will typically be 8- or 9-membered azabicyclo compounds.
  • the azabicyclo ring contains a carbon-carbon double bond between two adjacent ring atoms.
  • the bulk-providing moiety is a cyclic substituent, which may be aromatic, alicyclic, or a combination thereof, may contain 0, 1 , 2, 3 or more heteroatoms, 0, 1 , 2, 3, 4 or more fused rings, and may be further substituted with 0, 1 , 2, 3, 4, 5 or more substituents.
  • the bulk-providing moiety on the azabicyclic ring may be a substituted or unsubstituted heterocyclic moiety.
  • the heterocyclic group may be a 3-, 4-, 5-, 6-, 7-, or higher-membered cyclic group and may contain 1 , 2, 3 or more heteroatoms.
  • the heterocyclic group may be substituted with 0, 1 , 2, 3, 4, 5 or more substituents, any two or more of which may be linked such that the heterocyclic group contains fused rings. Therefore, the heterocyclic group may consist of 1 , 2, 3 or more rings, any of which may be aromatic or alicyclic.
  • the azabicyclic ring may be connected to any atom within the heterocyclic group, and multiple points of attachment, such that the azabicyclic ring and the heterocyclic group form a cycle, are within the scope of the disclosure.
  • heterocyclic groups include tetrahydropyranyl, pyridinyl, quinolinyl, isoquinolinyl, morpholinyl, azetidinyl, azetidinonyl, imidazolyl, dihydroimidazo, piperidinyl, piperizinyl, indolyl, dihydroindolyl, dihydroindolinonyl, pyrrolyl, pyrrolidinonyl, pyrrolidinyl, thienyl, benzothienyl, bipyridinyl, thiazolyl, aza-phenanthrenyl, pyrazinyl, pyrimidyl, furanyl, benzofuranyl,
  • the bulk-providing moiety may further be an aryl moiety substituted with a nitrogen-containing group (herein referred to as a "N-substituted aryl moiety").
  • the bulk-providing moiety comprises a moiety having the structure of formula (II)
  • V, W, X, and Y are independently selected from N and CR'", wherein R'" is selected from H, hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, substituted heteroatom-containing hydrocarbyl, and functional groups;
  • R" is selected from H, Ci-Ci 0 alkyl, C ⁇ -C ⁇ o acyl, C 5 -Ci 2 aryl, nitrogen protecting groups, and further wherein R" may connect with the aryl moiety to form a further cyclic structure;
  • the bulk-providing moiety has the structure of formula (III)
  • the bulk providing moiety is substituted or unsubstituted indolinyl-2-one.
  • the indolinyl-2-one may be substituted with 0, 1 , 2, 3, 4, 5 or more substituents at any position.
  • any two or more substituents on the indolinyl-2- one may be taken together to form a cyclic structure comprising 1 , 2, 3 or more rings, wherein the cyclic structure may be alicyclic, aromatic, or a combination thereof and may contain 0, 1 , 2, 3 or more heteroatoms.
  • Q is selected from H, hydrocarbyl, substituted hydrocarbyl, heteroatom-containing hydrocarbyl, substituted heteroatom-containing hydrocarbyl, and functional groups.
  • a linking moiety is optionally present between the azabicyclo ring and the bulk- providing moiety.
  • the linking moiety may be attached to the azabicyclo ring and/or the bulk-providing moiety at more than one location, such that the linking moiety forms a cycle with the azabicyclo ring and/or the bulk-providing moiety.
  • the linking moiety is present, and is a group selected from hydrocarbylene, substituted hydrocarbylene, heteroatom-containing hydrocarbylene, substituted heteroatom-containing hydrocarbylene, and functional groups.
  • linking moieties include substituted or unsubstituted Ci-C 20 alkylene, C 2 -C 20 alkenylene, C 2 -C 20 alkynylene, C 5 -C 24 arylene, C 6 -C 24 alkarylene, and C 6 -C 24 aralkylene. Further examples of linking moieties include substituted or unsubstituted C 1 -C 20 heteroatom-containing alkylene, C 2 -C 20 heteroatom-containing alkenylene, C 2 -C 20 heteroatom-containing alkynylene, C 5 -C 24 heteroatom-containing arylene, C 6 -C 24 heteroatom-containing alkarylene, and C 6 -C 24 heteroatom-containing aralkylene.
  • linking groups include functional groups such as amide, imide, thio, oxa, aza, sila, and oxo.
  • Specific examples of linking groups include -(CH 2 J n -, -(OCH 2 ) n -, -(OCH 2 CH 2 V, -(OCH 2 CH(CH 3 )V, -O-, -S-, -NR'-, -(CO)-, -(CO)-O-, -0-(CO)-, -0-(CO)-O-, -(CH 2 VNR'-, -NR'-(CH 2 ) n -, -(CO)-NR'-, -NR'-(CO)-, -0-(CO)-NR'-, -NR'-(CO)-O-, -S-S-, -S-(CO)-, and -(CO)-S-, where n is an integer between 1 and 10, and R' is selected from H, al
  • the linking moiety is a nitrogen-containing moiety.
  • the linking moiety is a nitrogen-containing moiety comprising a secondary or tertiary amine, or the nitrogen-containing moiety is an amide, or the nitrogen-containing moiety is other than an amide.
  • the linking moiety is a carbonyl- containing moiety.
  • the linking moiety is a carbonyl-containing moiety comprising a ketone or carbonate, or the carbonyl containing moiety is an ester, or the carbonyl-containing moiety is other than an ester.
  • any asymmetric moiety described herein or known in the art may be incorporated into the compounds of the disclosure in any appropriate fashion.
  • the linking moiety is absent such that the azabicyclo ring is directly connected to the bulk-providing moiety.
  • the bulk-providing moiety is an indolinyl-2-one moiety.
  • the azabicyclo ring may be connected to the 1 -position (i.e., the nitrogen atom at the 1 -position) or 3-position (i.e., the carbon atom at the 3-position) of the indolinyl-2-one.
  • the azabicyclo ring may be connected to a position on the aryl portion of the indolinyl-2-one.
  • multiple connections between the azabicyclo ring and the indolinyl-2-one, such that the azabicylco ring and the indolinyl-2- one together form a ring are within the scope of the disclosure.
  • Examples of the compounds of the disclosure comprising an azabicyclo ring substituted with indolinyl-2-one include compounds with the structure of formula (IV)
  • p, q, and m are integers independently selected from zero or 1 ;
  • B 1 , B 2 , and D 1 are independently selected from N and CR 10 ;
  • Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , Q 6 , and Q 7 are independently selected from NR 1 and CR 8 R 9 , provided that the bicyclic ring defined by Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , Q 6 , Q 7 B 1 , B 2 , and D 1 contains at least one nitrogen ring atom;
  • L is a linker moiety selected from -NH-, -NR 1 '-CO-, -NR 1 '-L 1 -, -CO-NR 1 '-, and
  • L 1 is selected from substituted and unsubstituted Ci-Ci 2 alkylene, substituted and unsubstituted C 2 -Ci 2 alkenylene, substituted and unsubstituted C 2 -Ci 2 alkynylene, and substituted and unsubstituted C 5 -Ci 2 arylene; and
  • R 1 is as described previously, and R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 1 ' are independently selected from H, hydrocarbyl, substituted hydrocarbyl, substituted hydrocarbyl, and functional groups, provided that any two substituents in formula (I) may be linked to form a ring.
  • R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 1 1 may be H, substituted or unsubstituted C I -C I0 alkyl, substituted or unsubstituted C 2 -Ci O alkenyl, substituted or unsubstituted C 2 -C1 0 alkynyl, substituted or unsubstituted C 5 -C 20 aryl, substituted or unsubstituted C 5 -C 20 alkaryl, substituted or unsubstituted C 5 -C 20 aralkyl, substituted or unsubstituted heteroatom-containing Ci-Ci 0 alkyl, substituted or unsubstituted heteroatom- containing C 2 -CiO alkenyl, substituted or unsubstituted heteroatom-containing C 2 -Ci O alkynyl, substituted or unsubsti
  • R 2 , p, q, m, Q 1 , Q 2 , Q 3 , Q 4 , Q 5 , Q 6 , Q 7 , B 1 , B 2 , L, and D 1 are as defined previously.
  • any of the compounds described herein may be administered in the form of a salt, ester, amide, prodrug, conjugate, active metabolite, isomer, fragment, analog, or the like, provided that the salt, ester, amide, prodrug, conjugate, active metabolite, isomer, fragment, or analog is pharmaceutically acceptable and pharmacologically active in the present context.
  • Salts, esters, amides, prodrugs, conjugates, active metabolites, isomers, fragments, and analogs of the agents may be prepared using standard procedures known to those skilled in the art of synthetic organic chemistry and described, for example, by J. March, Advanced Organic Chemistry: Reactions, Mechanisms and Structure, 5th Edition (New York: Wiley-Interscience, 2001 ).
  • any of the compounds described herein may be in the form of a pharmaceutically acceptable salt.
  • a pharmaceutically acceptable salt may be prepared from any pharmaceutically acceptable organic acid or base, any pharmaceutically acceptable inorganic acid or base, or combinations thereof. The acid or base used to prepare the salt may be naturally occurring.
  • Suitable organic acids for preparing acid addition salts include, e.g., Ci-C 6 alkyl and C 6 -Ci 2 aryl carboxylic acids, di-carboxylic acids, and tri-carboxylic acids such as acetic acid, propionic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, glycolic acid, citric acid, pyruvic acid, oxalic acid, malic acid, malonic acid, benzoic acid, cinnamic acid, mandelic acid, salicylic acid, phthalic acid, and terephthalic acid, and aryl and alkyl sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, and p-toluenesulfonic acid, and the like.
  • Suitable inorganic acids for preparing acid addition salts include, e.g., hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, and the like.
  • An acid addition salt may be reconverted to the free base by treatment with a suitable base.
  • Suitable organic bases for preparing basic addition salts include, e.g., primary, secondary and tertiary amines, such as trimethylamine, triethylamine, tripropylamine, N,N- dibenzylethylenediamine, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, glucamine, glucosamine, histidine, and polyamine resins, cyclic amines such as caffeine, N- ethylmorpholine, N-ethylpiperidine, and purine, and salts of amines such as betaine, choline, and procaine, and the like.
  • primary, secondary and tertiary amines such as trimethylamine, triethylamine, tripropylamine, N,N- dibenzylethylenediamine, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, glucamine, glucosamine, histidine, and polyamine resins, cyclic
  • Suitable inorganic bases for preparing basic addition salts include, e.g., salts derived from sodium, potassium, ammonium, calcium, ferric, ferrous, aluminum, lithium, magnesium, or zinc such as sodium hydroxide, potassium hydroxide, calcium carbonate, sodium carbonate, and potassium carbonate, and the like.
  • a basic addition salt may be reconverted to the free acid by treatment with a suitable acid.
  • Preparation of esters involves transformation of a carboxylic acid group via a conventional esterification reaction involving nucleophilic attack of an RO " moiety at the carbonyl carbon. Esterification may also be carried out by reaction of a hydroxyl group with an esterification reagent such as an acid chloride.
  • Esters can be reconverted to the free acids, if desired, by using conventional hydrogenolysis or hydrolysis procedures.
  • Amides may be prepared from esters, using suitable amine reactants, or they may be prepared from an anhydride or an acid chloride by reaction with ammonia or a lower alkyl amine.
  • Prodrugs and active metabolites may also be prepared using techniques known to those skilled in the art or described in the pertinent literature. Prodrugs are typically prepared by covalent attachment of a moiety that results in a compound that is therapeutically inactive until modified by an individual's metabolic system.
  • any of the compounds of the disclosure may be the active agent in a formulation as described herein.
  • Formulations containing the compounds of the disclosure may include 1 , 2, 3 or more of the compounds described herein, and may also include one or more additional active agents.
  • the amount of active agent in the formulation typically ranges from about 0.05 wt% to about 95 wt% based on the total weight of the formulation.
  • the amount of active agent may range from about 0.05 wt% to about 50 wt%, or from about 0.1 wt% to about 25 wt%.
  • the amount of active agent in the formulation may be measured so as to achieve a desired dose, as described below.
  • Formulations containing the compounds of the disclosure may be presented in unit dose form or in multi-dose containers with an optional preservative to increase shelf life.
  • compositions of the disclosure may be administered to the patient by any appropriate method.
  • both systemic and localized methods of administration are acceptable.
  • selection of a method of administration will be influenced by a number of factors, such as the condition being treated, frequency of administration, dosage level, and the wants and needs of the patient. For example, certain methods may be better suited for rapid delivery of high doses of active agent, while other methods may be better suited for slow, steady delivery of active agent.
  • methods of administration that are suitable for delivery of the compounds of the disclosure include parental and transmembrane absorption (including delivery via the digestive and respiratory tracts). Formulations suitable for delivery via these methods are well known in the art.
  • formulations containing the compounds of the disclosure may be administered parenterally, such as via intravenous, subcutaneous, intraperitoneal, or intramuscular injection, using bolus injection and/or continuous infusion.
  • parenteral administration employs liquid formulations.
  • compositions may also be administered via the digestive tract, including orally and rectally.
  • formulations that are appropriate for administration via the digestive tract include tablets, capsules, pastilles, chewing gum, aqueous solutions, and suppositories.
  • formulations may also be administered via transmucosal administration.
  • Transmucosal delivery includes delivery via the oral (including buccal and sublingual), nasal, vaginal, and rectal mucosal membranes.
  • Formulations suitable for transmucosal deliver are well known in the art and include tablets, chewing gums, mouthwashes, lozenges, suppositories, gels, creams, liquids, and pastes.
  • the formulations may also be administered transdermally.
  • Transdermal delivery may be accomplished using, for example, topically applied creams, liquids, pastes, gels and the like as well as what is often referred to as transdermal "patches.”
  • the formulations may also be administered via the respiratory tract.
  • Pulmonary delivery may be accomplished via oral or nasal inhalation, using aerosols, dry powders, liquid formulations, or the like. Aerosol inhalers and imitation cigarettes are examples of pulmonary dosage forms.
  • Liquid formulations include solutions, suspensions, and emulsions.
  • solutions may be aqueous solutions of the active agent and may include one or more of propylene glycol, polyethylene glycol, and the like.
  • Aqueous suspensions can be made by dispersing the finely divided active agent in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well known suspending agents.
  • viscous material such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well known suspending agents.
  • formulations of solid form which are intended to be converted, shortly before use, to liquid form.
  • Tablets and lozenges may comprise, for example, a flavored base such as compressed lactose, sucrose and acacia or tragacanth and an effective amount of an active agent.
  • Pastilles generally comprise the active agent in an inert base such as gelatin and glycerine or sucrose and acacia.
  • Mouthwashes generally comprise the active agent in a suitable liquid carrier.
  • the chemical compound according to the disclosure may be formulated as ointments, creams or lotions, or as a transdermal patch.
  • Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents.
  • Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilising agents, dispersing agents, suspending agents, thickening agents, or colouring agents.
  • Transdermal patches typically comprise: (1) an impermeable backing layer which may be made up of any of a wide variety of plastics or resins, e.g. aluminized polyester or polyester alone or other impermeable films; and (2) a reservoir layer comprising, for example, a compound of the disclosure in combination with mineral oil, polyisobutylene, and alcohols gelled with USP hydroxymethylcellulose.
  • the reservoir layer may comprise acrylic-based polymer adhesives with resinous crosslinking agents which provide for diffusion of the active agent from the reservoir layer to the surface of the skin.
  • the transdermal patch may also have a delivery rate-controlling membrane such as a microporous polypropylene disposed between the reservoir and the skin.
  • Ethylene-vinyl acetate copolymers and other microporous membranes may also be used.
  • an adhesive layer is provided which may comprise an adhesive formulation such as mineral oil and polyisobutylene combined with the active agent.
  • Other typical transdermal patches may comprise three layers: (1 ) an outer layer comprising a laminated polyester film; (2) a middle layer containing a rate-controlling adhesive, a structural non-woven material and the active agent; and (3) a disposable liner that must be removed prior to use.
  • Transdermal delivery systems may also involve incorporation of highly lipid soluble carrier compounds such as dimethyl sulfoxide (DMSO), to facilitate penetration of the skin.
  • DMSO dimethyl sulfoxide
  • Other carrier compounds include lanolin and glycerin.
  • Rectal or vaginal suppositories comprise, for example, an active agent in combination with glycerin, glycerol monopalmitate, glycerol, monostearate, hydrogenated palm kernel oil and fatty acids.
  • an active agent in combination with glycerin, glycerol monopalmitate, glycerol, monostearate, hydrogenated palm kernel oil and fatty acids.
  • Another example of a suppository formulation includes ascorbyl palmitate, silicon dioxide, white wax, and cocoa butter in combination with an effective amount of an active agent.
  • Nasal spray formulations may comprise a solution of active agent in physiologic saline or other pharmaceutically suitable carder liquids.
  • Nasal spray compression pumps are also well known in the art and can be calibrated to deliver a predetermined dose of the solution.
  • Aerosol formulations suitable for pulmonary administration include, for example, formulations wherein the active agent is provided in a pressurized pack with a suitable propellant.
  • Suitable propellants include chlorofluorocarbons (CFCs) such as dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide, or other suitable gases.
  • CFCs chlorofluorocarbons
  • the aerosol may also contain a surfactant such as lecithin.
  • the dose of drug may be controlled by provision of a metered valve.
  • Dry powder suitable for pulmonary administration include, for example, a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).
  • the powder carrier will form a gel in the nasal cavity.
  • Unit doses for dry powder formulations may be, for example, in the form of capsules or cartridges of, e.g., gelatin, or blister packs from which the powder may be administered by means of an inhaler.
  • additives include acids, antioxidants, antimicrobials, buffers, colorants, crystal growth inhibitors, defoaming agents, diluents, emollients, fillers, flavorings, gelling agents, fragrances, lubricants, propellants, thickeners, salts, solvents, surfactants, other chemical stabilizers, or mixtures thereof.
  • acids antioxidants, antimicrobials, buffers, colorants, crystal growth inhibitors, defoaming agents, diluents, emollients, fillers, flavorings, gelling agents, fragrances, lubricants, propellants, thickeners, salts, solvents, surfactants, other chemical stabilizers, or mixtures thereof.
  • the amount of active agent in formulations that contain the compounds of the disclosure may be calculated to achieve a specific dose (i.e., unit weight of active agent per unit weight of patient) of active agent.
  • the treatment regimen may be designed to sustain a predetermined systemic level of active agent.
  • formulations and treatment regimen may be designed to provide an amount of active agent that ranges from about 0.001 mg/kg/day to about 100 mg/kg/day for an adult.
  • the amount of active agent may range from about 0.1 mg/kg/day to about 50 mg/kg/day, about 0.1 mg/kg/day to about 25 mg/kg/day, or about 1 mg/kg/day to about 10 mg/kg/day.
  • dosages may vary depending on a variety of factors, including method and frequency of administration, physical characteristics of the patient, level of drug addiction of the patient, duration of treatment regimen, and the severity of withdrawal symptoms that are experienced by the patient.
  • Treatment regimens that make use of multiple methods of administration are within the scope of the disclosure.
  • a small, steady dose of the compounds of the disclosure may be administered continuously via transdermal patch, while an additional dose can be administered as needed by the patient via chewing gum.
  • the compounds of the disclosure are ligands for one or more of the neuronal nicotinic acetylcholine receptors (nAChRs), a group of receptors that includes, for example, ⁇ 3 ⁇ 4, ⁇ 3 ⁇ 5 ⁇ 4, ⁇ 3 ⁇ 5 ⁇ 2 ⁇ 4, ⁇ 4 ⁇ 2, ⁇ 4 ⁇ 5 ⁇ 2, ⁇ 7, and ⁇ 9*.
  • nAChRs neuronal nicotinic acetylcholine receptors
  • the compounds of the disclosure may be competitive or noncompetitive with endogenous ligands, and may further exhibit agonistic or antagonistic activity. In addition to their ability to bind to one or more nAChRs, the compounds of the disclosure may also be either agonists or antagonists.
  • the compounds of the disclosure may have a high binding affinity for one or more nAChR.
  • the compounds may have binding coefficient values (i.e., K 1 ) for any of the abovementioned nAChRs that are less than about 1000, less than about 700, less than about 500, less than about 300, less than about 200, less than about 100, less than about 50, less than about 30, less than about 10, less than about 5, less than about 3, or less than about 2.
  • the compounds may further be selective ligands for any one or combination of the neuronal nAChRs.
  • the compounds are selective for ⁇ 3 ⁇ 4, ⁇ 4 ⁇ 2, ⁇ 7, or any combination thereof over other nAChRs.
  • the compounds may be selective for ⁇ 3 ⁇ 4 and ⁇ 4 ⁇ 2 nAChRs over other nAChRs.
  • the compounds are selective for the ⁇ 3 ⁇ 4 nAChR, and in yet another example, the compounds are selective for the ⁇ 4 ⁇ 2 nAChR.
  • the compounds of the disclosure are useful in methods of treating patients suffering from chemical addictions.
  • Patients with chemical addictions that may be treated with the compounds, compositions, and methods disclosed herein include patients addicted to nicotine, opioids, cocaine, and the like.
  • the compounds may be used, for example, in aiding smoking cessation.
  • the compounds may be used alone or in combination with other nicotine-addiction treatment methods.
  • the compounds of the disclosure are analgesics, and are useful in the treatment of pain and in certain pain therapy regimens.
  • the compounds disclosed herein are useful in the treatment of patients suffering from Parkinson's Disease, Alzheimer's Disease, neurodegenerative disorders, and the like.
  • the compounds of the disclosure may be prepared using synthetic methods as exemplified in the experimental section herein, as well as standard procedures that are known to those skilled in the art of synthetic organic chemistry and used for the preparation of analogous compounds. Appropriate synthetic procedures may be found, for example, in J. March, Advanced Organic Chemistry: Reactions, Mechanisms and Structure, 5th Edition (New York: Wiley-Interscience, 2001 ). Syntheses of representative compounds are detailed in the Examples.
  • Reagents and reaction conditions a. aniline, molecular sieves, toluene, reflux, sodium cyanoborohydride, methanol; b. chloroacetyl chloride, triethylamine, methylene chloride, reflux; c. aluminum chloride, 130-16CTC.
  • Reagents and reaction conditions a. NaN(TMS) 2 , N-(5-chloro-2-pyridyl)triflimide, THF, -78°C; b. 3-pyridineboronic acid, Pd(PPh ⁇ ) 4 , KiPO 4 , dioxane, 85°C.
  • Reagents and reaction conditions a. ethyl chloroformate, K 2 CO 3 , toluene, 90 - 100°C; b. NaN(TMS) 2 , N-(5-chloro-2-pyridyl)triflimide, THF, -78°C; c. 3-pyridineboronic acid, Pd(PPh,),,, K,PO 4 , dioxane, 85°C; d. LAH, THF.
  • Ki ⁇ SEM was determined for each compound in competition with [ H]epibatidine.
  • Compounds are tested on membranes derived from HEK cells that have been transfected with rat ⁇ 3 ⁇ 4 and ⁇ 4 ⁇ 2 receptors. Specific experiments are described below:
  • KX ⁇ 3 ⁇ 4R2 and KX ⁇ 4 ⁇ 2R2 cells are cultured in Dulbecco's modified Eagle's medium (DMEM), supplemented with 10% fetal bovine serum (FBS), 0.5% penicillin/streptomycin, and 0.4 mg/ml of geneticin.
  • DMEM Dulbecco's modified Eagle's medium
  • FBS fetal bovine serum
  • penicillin/streptomycin 0.5% penicillin/streptomycin
  • 0.4 mg/ml of geneticin The cells are maintained in an atmosphere of 7.5% CO 2 in a humidified incubator at 37°C.
  • binding assays cells are plated on 100-mm dishes.
  • the cells are seeded into 96-well collagen- coated plates (Becton Dickinson Biocoat) at a density of approximately 50,000 cells/well. Cells seeded at this density grow into a confluent monolayer in 24 to 30 h.
  • Binding Assays Cells are harvested by scraping the plates with a rubber policeman and then centrifuged at 500 x g (2200 rpm) for 10 min. The cell pellet is suspended in Tris buffer, homogenized in a Polytron Homogenizer, and centrifugation repeated twice at 20,000 x g (13,500 rpm) for 20 min. Cells are finally suspended in 5 ml of Tris buffer to determine their protein content. For binding, the cell membrane is incubated with the test compounds at concentrations ranging from 10 "5 to 10 "10 M in the presence of 0.3 nM of [ HJepibatidine.
  • L radioligand concentration
  • Kj is the binding affinity of the radioligand, as determined previously by saturation analysis.
  • Table 1 provides the structures of compounds that were screened for their binding affinities.

Landscapes

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

Abstract

L'invention porte sur des composés capables de moduler sélectivement ou non sélectivement les récepteurs nicotiniques de l'acétylcholine. Les composés, compositions et procédés décrits ici sont utiles, par exemple, dans le traitement de patients souffrant de divers états médicaux comprenant une douleur, des addictions à des produits chimiques, la maladie de Parkinson, la maladie d'Alzheimer et des troubles neurodégénératifs. Dans un mode de réalisation, les composés comprennent un noyau azabicyclo à 7 à 11 chaînons.
PCT/US2007/023152 2007-11-02 2007-11-02 Modulateurs des récepteurs nicotiniques de l'acétylcholine WO2009058120A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/US2007/023152 WO2009058120A1 (fr) 2007-11-02 2007-11-02 Modulateurs des récepteurs nicotiniques de l'acétylcholine

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US2007/023152 WO2009058120A1 (fr) 2007-11-02 2007-11-02 Modulateurs des récepteurs nicotiniques de l'acétylcholine

Publications (1)

Publication Number Publication Date
WO2009058120A1 true WO2009058120A1 (fr) 2009-05-07

Family

ID=39651385

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2007/023152 WO2009058120A1 (fr) 2007-11-02 2007-11-02 Modulateurs des récepteurs nicotiniques de l'acétylcholine

Country Status (1)

Country Link
WO (1) WO2009058120A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011085389A1 (fr) * 2010-01-11 2011-07-14 Astraea Therapeutics, Llc Modulateurs du récepteur nicotinique de l'acétylcholine
US8987453B2 (en) 2006-11-06 2015-03-24 Abbvie Inc. Azaadamantane derivatives and methods of use
US9464078B2 (en) 2010-09-23 2016-10-11 Abbvie Inc. Monohydrate of azaadamantane derivatives

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998054182A1 (fr) * 1997-05-30 1998-12-03 Neurosearch A/S Derives de 9-azabicyclo(3.3.1)non-2-ene et nonane utilises comme ligands cholinergiques de recepteurs nicotiniques de l'ach.
WO2000032600A1 (fr) * 1998-11-27 2000-06-08 Neurosearch A/S Derives de 8-azabicyclo[3.2.1]oct-2-ene et de 8-azabicyclo[3.2.1]octane
WO2000045846A1 (fr) * 1999-02-02 2000-08-10 Sanofi-Synthelabo Compositions pharmaceutiques contenant de la nicotine ou un ligand des recepteurs nicotiniques et un inhibiteur de la monamine oxydase et leur application dans le sevrage tabagique
WO2005037832A2 (fr) * 2003-10-15 2005-04-28 Targacept, Inc. Compositions pharmaceutiques et methodes destinees au soulagement de la douleur et au traitement de troubles du systeme nerveux central
WO2005060947A2 (fr) * 2003-12-19 2005-07-07 Sri International Ligands agonistes et antagonistes du recepteur de la nociceptine
US20050250808A1 (en) * 2004-04-22 2005-11-10 Wenge Xie Indoles, 1h-indazoles, 1,2-benzisoxazoles, 1,2-benzoisothiazoles, and preparation and uses thereof

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998054182A1 (fr) * 1997-05-30 1998-12-03 Neurosearch A/S Derives de 9-azabicyclo(3.3.1)non-2-ene et nonane utilises comme ligands cholinergiques de recepteurs nicotiniques de l'ach.
WO2000032600A1 (fr) * 1998-11-27 2000-06-08 Neurosearch A/S Derives de 8-azabicyclo[3.2.1]oct-2-ene et de 8-azabicyclo[3.2.1]octane
WO2000045846A1 (fr) * 1999-02-02 2000-08-10 Sanofi-Synthelabo Compositions pharmaceutiques contenant de la nicotine ou un ligand des recepteurs nicotiniques et un inhibiteur de la monamine oxydase et leur application dans le sevrage tabagique
WO2005037832A2 (fr) * 2003-10-15 2005-04-28 Targacept, Inc. Compositions pharmaceutiques et methodes destinees au soulagement de la douleur et au traitement de troubles du systeme nerveux central
WO2005060947A2 (fr) * 2003-12-19 2005-07-07 Sri International Ligands agonistes et antagonistes du recepteur de la nociceptine
US20050250808A1 (en) * 2004-04-22 2005-11-10 Wenge Xie Indoles, 1h-indazoles, 1,2-benzisoxazoles, 1,2-benzoisothiazoles, and preparation and uses thereof

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8987453B2 (en) 2006-11-06 2015-03-24 Abbvie Inc. Azaadamantane derivatives and methods of use
WO2011085389A1 (fr) * 2010-01-11 2011-07-14 Astraea Therapeutics, Llc Modulateurs du récepteur nicotinique de l'acétylcholine
CN102905527A (zh) * 2010-01-11 2013-01-30 阿斯特来亚治疗有限责任公司 烟碱型乙酰胆碱受体调节剂
JP2013516496A (ja) * 2010-01-11 2013-05-13 アストライア セラピューティクス， エルエルシー ニコチン性アセチルコリン受容体モジュレーター
US9062042B2 (en) 2010-01-11 2015-06-23 Astraea Therapeutics, Llc Nicotinic acetylcholine receptor modulators
RU2560729C2 (ru) * 2010-01-11 2015-08-20 АСТРАЕА ТЕРАПЕУТИКС, ЭлЭлСи Модуляторы никотиновых ацетилхолиновых рецепторов
CN102905527B (zh) * 2010-01-11 2016-08-24 阿斯特来亚治疗有限责任公司 烟碱型乙酰胆碱受体调节剂
US9670198B2 (en) 2010-01-11 2017-06-06 Astraea Therapeutics, Llc Nicotinic acetylcholine receptor modulators
US9464078B2 (en) 2010-09-23 2016-10-11 Abbvie Inc. Monohydrate of azaadamantane derivatives

Similar Documents

Publication Publication Date Title
Zimmerman et al. Discovery of a potent, peripherally selective trans-3, 4-dimethyl-4-(3-hydroxyphenyl) piperidine opioid antagonist for the treatment of gastrointestinal motility disorders
JP3276111B2 (ja) Ｏｒｌ１−レセプターアゴニストとしての２−ベンズイミダゾリルアミン化合物
AU692788B2 (en) Piperazine compounds used in therapy
JP6847093B2 (ja) ムスカリン様アゴニスト
EP2655332B1 (fr) Nouveaux morphinanes utiles en tant qu&#39;analgésiques
US6861425B2 (en) Benzimidazole compounds as ORL1-receptor agonists
US8110584B2 (en) Methods for the treatment of respiratory depression
EP1833804A1 (fr) Modulateurs de type arylsulfonamide
BRPI0708843A2 (pt) composto, composiÇço farmacÊutica, e, uso do composto
US20080051441A1 (en) Aryl Sulphonamide Modulators
WO2006124687A1 (fr) Agents selectifs en fonction du sous-type de recepteurs d&#39;opiates
JPH09505036A (ja) 喘息治療用のニューロキニン２受容体拮抗薬としての新規な４−ピペリジニル置換ラクタム
CA2598416C (fr) Ligands du recepteur opioide kappa
US8697722B2 (en) Nicotinic acetylcholine receptor modulators
BR112012024785B1 (pt) antagonista do receptor de cgrp, seu uso e composição farmacêutica que o compreende
PT2205558E (pt) Amidas de n-fenil-pirrolidinilmetilpirrolidina substituídas e sua utilização terapêutica como moduladores do receptor h3 da histamina
WO2005060947A2 (fr) Ligands agonistes et antagonistes du recepteur de la nociceptine
EP3077398B1 (fr) Nouveaux composés opioïdes et leurs utilisations
ES2351148T3 (es) Nuevos derivados de bencimidazol imidazo-piridina y su utilización como medicamento.
WO2009058120A1 (fr) Modulateurs des récepteurs nicotiniques de l&#39;acétylcholine
FR2873690A1 (fr) Derives d&#39;oxopiperidine, leur preparation et leur application en therapeutique
US5981540A (en) Heterocycle-condensed morphinoid derivatives
EP2233140A1 (fr) Bizyklische Amide zur Verbesserung der glutamatergischen Synapsenreaktionen
US6054474A (en) Heterocyclic compounds for the treatment of pain and use thereof
JP2560083B2 (ja) 心血管系の治療において活性な化合物

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 07867342

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 07867342

Country of ref document: EP

Kind code of ref document: A1