WO2007024814A1 - HETEROARYL-SUBSTiTUTED DIAZATRICYCLOALKANES, METHODS FOR ITS PREPARATION AND USE THEREOF - Google Patents
HETEROARYL-SUBSTiTUTED DIAZATRICYCLOALKANES, METHODS FOR ITS PREPARATION AND USE THEREOF Download PDFInfo
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- WO2007024814A1 WO2007024814A1 PCT/US2006/032685 US2006032685W WO2007024814A1 WO 2007024814 A1 WO2007024814 A1 WO 2007024814A1 US 2006032685 W US2006032685 W US 2006032685W WO 2007024814 A1 WO2007024814 A1 WO 2007024814A1
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- diazatricyclo
- undecane
- pyridin
- carbamoyl
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- OUSWGZBGFGZRKB-UHFFFAOYSA-N C1NC2C(CC3)CCN3C2C1c1cnccc1 Chemical compound C1NC2C(CC3)CCN3C2C1c1cnccc1 OUSWGZBGFGZRKB-UHFFFAOYSA-N 0.000 description 1
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- 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
- C07D471/12—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 three hetero rings
- C07D471/18—Bridged systems
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- 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
- A61K31/439—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 the ring forming part of a bridged ring system, e.g. quinuclidine
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- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- 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
- C07D471/12—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 three hetero rings
- C07D471/14—Ortho-condensed systems
Definitions
- the present invention relates to pharmaceutical compositions incorporating compounds capable of affecting nicotinic acetylcholinergic receptors (nAChRs), for example, as modulators of specific nicotinic receptor subtypes (specifically, the ⁇ 7 nAChR subtype).
- nAChRs nicotinic acetylcholinergic receptors
- the present invention also relates to methods for treating a wide variety of conditions and disorders, particularly those associated with dysfunction of the central and autonomic nervous systems.
- Nicotine has been proposed to have a number of pharmacological effects. See, for example, Pullan et al., N. Engl. J. Med. 330: 811 (1994). Certain of those effects may be related to effects upon neurotransmitter release. See, for example, Sjak-shie et al., Brain Res. 624: 295 (1993), where neuroprotective effects of nicotine are proposed. Release of acetylcholine and dopamine by neurons, upon administration of nicotine, has been reported by Rowell et al., J. Neurochem. 43: 1593 (1984); Rapier et al., J. Neurochem. 50: 1123 (1988); Sandor et al., Brain Res. 567: 313 (1991) and Vizi, Br.
- Nicotinic compounds are reported as being particularly useful for treating a wide variety of CNS disorders. Indeed, a wide variety of compounds have been reported to have therapeutic properties. See, for example, Bencherif and Schmitt, Current Drug Targets: CNS and Neurological Disorders 1(4): 349 (2002); Levin and Rezvani, Current Drug Targets: CNS and Neurological Disorders 1(4): 423 (2002); O'Neill et al., Current Drug Targets: CNS and Neurological Disorders 1(4): 399 (2002); U.S. Patent Nos.
- CNS disorders are a type of neurological disorder.
- CNS disorders can be drug induced; can be attributed to genetic predisposition, infection or trauma; or can be of unknown etiology.
- CNS disorders comprise neuropsychiatric disorders, neurological diseases and mental illnesses, and include neurodegenerative diseases, behavioral disorders, cognitive disorders and cognitive affective disorders.
- CNS disorders whose clinical manifestations have been attributed to CNS dysfunction (i.e., disorders resulting from inappropriate levels of neurotransmitter release, inappropriate properties of neurotransmitter receptors, and/or inappropriate interaction between neurotransmitters and neurotransmitter receptors).
- CNS disorders can be attributed to a deficiency of choline, dopamine, norepinephrine and/or serotonin.
- Relatively common CNS disorders include pre-senile dementia (early- onset Alzheimer's disease), senile dementia (dementia of the Alzheimer's type), micro-infarct dementia, AIDS-related dementia, Creutzfeldt-Jakob disease, Pick's disease, Parkinsonism including Parkinson's disease, Lewy body dementia, progressive supranuclear palsy, Huntington's chorea, tardive dyskinesia, hyperkinesia, mania, attention deficit disorder, anxiety, dyslexia, schizophrenia, depression, obsessive-compulsive disorders and Tourette's syndrome.
- nAChRs characteristic of the CNS have been shown to occur in several subtypes, the most common of which are the ⁇ 4 ⁇ 2 and ⁇ 7 subtypes. See, for example, Schmitt, Current Med. Chem. 7: 749 (2000).
- Ligands that interact with the ⁇ 7 nAChR subtype have been proposed to be useful in the treatment of schizophrenia.
- Nicotine improves sensory gating deficits in animals and schizophrenics.
- Blockade of the ⁇ 7 nAChR subtype induces a gating deficit similar to that seen in schizophrenia. See, for example, Leonard et al., Schizophrenia Bulletin 22(3): 431 (1996). Biochemical, molecular, and genetic studies of sensory processing, in patients with the P50 auditory-evoked potential gating deficit, suggest that the ⁇ 7 nAChR subtype may function in an inhibitory neuronal pathway. See, for example, Freedman et al., Biological Psychiatry 38(1): 22 (1995).
- ⁇ 7 nAChRs have been proposed to be mediators of angiogenesis, as described by Heeschen et al., J. Clin. Invest. 100: 527 (2002). In these studies, inhibition of the ⁇ 7 subtype was shown to decrease inflammatory angiogenesis. Also, ⁇ 7 nAChRs have been proposed as targets for controlling neurogenesis and tumor growth (Utsugisawa et al., Molecular Brain Research. 106(1- 2): 88 (2002) and U.S. Patent Application 2002/0016371).
- nAChR subtypes that have the potential to induce undesirable side effects (e.g., appreciable activity at cardiovascular and skeletal muscle receptor sites).
- a pharmaceutical composition incorporating a compound which interacts with nicotinic receptors but not muscarinic receptors, as the latter are associated with side effects, such as hypersalivation, sweating, tremors, cardiovascular and gastrointestinal disturbances, related to the function of the parasympathetic nervous system (see Caulfield, Pharmacol. Ther. 58: 319 (1993) and Broadley and Kelly, Molecules 6: 142 (2001)).
- compositions which are selective for the ⁇ 7 nAChR subtype, for the treatment of certain conditions or disorders (e.g., schizophrenia, cognitive disorders, and neuropathic pain) and for the prevention of tissue damage and the hastening of healing (i.e., for neuroprotection and the control of angiogenesis).
- certain conditions or disorders e.g., schizophrenia, cognitive disorders, and neuropathic pain
- tissue damage and the hastening of healing i.e., for neuroprotection and the control of angiogenesis.
- the present invention provides such compounds, compositions and methods.
- the present invention relates to amide and urea derivatives of heteroaryl- substituted diazatricycloalkanes, pharmaceutical compositions including the compounds, methods of preparing the compounds, and methods of treatment using the compounds. More specifically, the methods of treatment involve modulating the activity of the ⁇ 7 nAChR subtype by administering one or more of the compounds to treat or prevent disorders mediated by the ⁇ 7 nAChR subtype.
- the diazatricycloalkanes typically consist of 1-azabicyclooctane fused to pyrrolidine ring.
- the substituent heteroaryl groups are 5- or 6-membered ring heteroaromatics, such as 3- ⁇ yridinyl and 5-pyrimidinyl moieties, which are attached directly to the diazatricycloalkane.
- the secondary nitrogen of the pyrrolidine moiety is substituted with an arylcarbonyl (amide type derivative) or an arylaminocarbonyl (N-arylcarbamoyl) (urea type derivative) group.
- the compounds are beneficial in therapeutic applications requiring a selective interaction at certain nAChR subtypes. That is, the compounds modulate the activity of certain nAChR subtypes, particularly the ⁇ 7 nAChR subtype, and do not have appreciable activity toward muscarinic receptors.
- the compounds can be administered in amounts sufficient to affect the functioning of the central nervous system (CNS) without significantly affecting those receptor subtypes that have the potential to induce undesirable side effects (e.g., without appreciable activity at ganglionic and skeletal muscle nAChR sites and at muscarinic receptors).
- the compounds are therefore useful towards modulating release of ligands involved in neurotransmission, without appreciable side effects.
- the compounds can be used as therapeutic agents to treat and/or prevent disorders characterized by an alteration in normal neurotransmitter release. Examples of such disorders include certain CNS conditions and disorders.
- the compounds can provide neuroprotection, treat patients susceptible to convulsions, treat depression, autism, and certain neuroendocrine disorders, and help manage stroke patients.
- the compounds also are useful in treating hypertension, type II diabetes and neoplasia and effecting weight loss.
- the compounds are selective for the ⁇ 7 nAChR subtype, they can be used to treat certain conditions or disorders (e.g., schizophrenia, cognitive disorders, and neuropathic pain), prevent tissue damage, and hasten healing (i.e., provide neuroprotection and control of angiogenesis).
- the pharmaceutical compositions provide therapeutic benefit to individuals suffering from such conditions or disorders and exhibiting clinical manifestations of such conditions or disorders.
- the compounds, administered with the pharmaceutical compositions can be employed in effective amounts to (i) exhibit nicotinic pharmacology and affect relevant nAChR sites (e.g., act as a pharmacological agonists at nicotinic receptors), and (ii) modulate neurotransmitter secretion, and hence prevent and suppress the symptoms associated with those diseases.
- the compounds have the potential to (i) increase the number of nAChRs of the brain of the patient, (ii) exhibit neuroprotective effects and (iii) when employed in effective amounts, not cause appreciable adverse side effects (e.g., significant increases in blood pressure and heart rate, significant negative effects upon the gastro-intestinal tract, and significant effects upon skeletal muscle).
- the pharmaceutical compositions are believed to be safe and effective with regards to prevention and treatment of various conditions or disorders.
- Y is either oxygen or sulfur, and Z is either nitrogen (i.e., NR') or a covalent bond.
- Ar is an aryl group, either carbocyclic or heterocyclic, either monocyclic or fused polycyclic, unsubstituted or substituted; and Cy is a 5- or 6-membered heteroaromatic ring, unsubstituted or substituted.
- the junction between the azacycle and the azabicycle can be characterized by any of the various relative and absolute stereochemical configurations at the junction sites (e.g., cis or trans, R or S).
- the invention further includes pharmaceutically acceptable salts thereof.
- the compounds have one or more asymmetric carbons and can therefore exist in the form of racemic mixtures, enantiomers and diastereomers.
- some of the compounds exist as E and Z isomers about a carbon-carbon double bond. All these individual isomeric compounds and their mixtures are also intended to be within the scope of the present invention.
- the invention includes compounds in which Ar is linked to the diazatricycle, at the nitrogen of the pyrrolidine ring, by a carbonyl group-containing functionality, forming an amide or a urea functionality.
- Ar may be bonded directly to the carbonyl group-containing functionality or may be linked to the carbonyl group- containing functionality through linker A.
- the invention includes compounds that contain a diazatricycle, containing a l-azabicyclo[2.2.2]octane.
- alkoxy includes alkyl groups from 1 to 8 carbon atoms in a straight or branched chain, also C 3-8 cycloalkyl, bonded to an oxygen atom.
- alkyl includes straight chain and branched Ci -8 alkyl, preferably C 1-6 alkyl.
- Substituted alkyl defines alkyl substituents with 1-3 substituents as defined below in connection with Ar and Cy.
- arylalkyl refers to moieties, such as benzyl, wherein an aromatic is linked to an alkyl group that is linked to the indicated position in the compound of Formulas 1 or 2.
- “Substituted arylalkyl” defines arylalkyl substituents with 1-3 substituents as defined below in connection with Ar and Cy.
- aromatic refers to 3- to 10-membered, preferably 5- and 6- membered, aromatic and heteroaromatic rings and polycyclic aromatics including 5- and/or 6-membered aromatic and/or heteroaromatic rings.
- aryl includes both carbocyclic and heterocyclic aromatic rings, both monocyclic and fused polycyclic, where the aromatic rings can be 5- or 6- membered rings.
- Representative monocyclic aryl groups include, but are not limited to, phenyl, furanyl, pyrrolyl, thienyl, pyridinyl, pyrimidinyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl and the like.
- Fused polycyclic aryl groups are those aromatic groups that include a 5- or 6-membered aromatic or heteroaromatic ring as one or more rings in a fused ring system.
- fused polycyclic aryl groups include naphthalene, anthracene, indolizine, indole, isoindole, benzofuran, benzothiophene, indazole, benzimidazole, benzthiazole, purine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8- naphthyridine, pteridine, carbazole, acridine, phenazine, phenothiazine, phenoxazine, and azulene.
- Cy are 5- and 6-membered ring heteroaromatic groups.
- Representative Cy groups include pyridinyl, pyrimidinyl, furanyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl and the like.
- cycloalkyl radicals contain from 3 to 8 carbon atoms.
- suitable cycloalkyl radicals include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
- polycycloalkyl radicals are selected from adamantyl, bornanyl, norbornanyl, bornenyl and norbornenyl.
- halogen is chlorine, iodine, fluorine or bromine.
- heteroaryl radicals are rings that contain from 3 to 10 members, preferably 5 or 6 members, including one or more heteroatoms selected from oxygen, sulfur and nitrogen.
- suitable 5-membered ring heteroaryl moieties include furyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, thienyl, tetrazolyl, and pyrazolyl.
- suitable 6-membered ring heteroaryl moieties include pyridinyl, pyrimidinyl, pyrazinyl, of which pyridinyl and pyrimidinyl are preferred.
- heterocyclic or “heterocyclyl” radicals include rings with 3 to 10 members, including one or more heteroatoms selected from oxygen, sulfur and nitrogen.
- suitable heterocyclic moieties include, but are not limited to, piperidinyl, morpholinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, isothiazolidinyl, thiazolidinyl, isoxazolidinyl, oxazolidinyl, piperazinyl, tetrahydropyranyl and tetrahydrofuranyl.
- Suitable pharmaceutically acceptable salts include inorganic acid addition salts such as chloride, bromide, sulfate, phosphate, and nitrate; organic acid addition salts such as acetate, galactarate, propionate, succinate, lactate, glycolate, malate, tartrate, citrate, maleate, fumarate, methanesulfonate, p-toluenesulfonate, and ascorbate; salts with acidic amino acid such as aspartate and glutamate; alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as magnesium salt and calcium salt; ammonium salt; organic basic salts such as trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, and N,N'-dibenzylethylenediamine salt; and salts with basic amino acid such as lysine salt and arginine salt.
- inorganic acid addition salts such as chlor
- the salts may be in some cases hydrates or ethanol solvates.
- Representative salts are provided as described in U.S. Patent Nos. 5,597,919 to Dull et al, 5,616,716 to Dull et al. and 5,663,356 to Ruecroft et al.
- neurotransmitters whose release is modulated (i.e., increased or decreased, depending on whether the compounds function as agonists, partial agonists or antagonists) by the compounds described herein include, but are not limited to, acetylcholine, dopamine, norepinephrine, serotonin and glutamate, and the compounds described herein function as modulators of one or more nicotinic receptors.
- an "agonist” is a substance that stimulates its binding partner, typically a receptor. Stimulation is defined in the context of the particular assay, or may be apparent in the literature from a discussion herein that makes a comparison to a factor or substance that is accepted as an "agonist” or an “antagonist” of the particular binding partner under substantially similar circumstances as appreciated by those of skill in the art. Stimulation may be defined with respect to an increase in a particular effect or function that is induced by interaction of the agonist or partial agonist with a binding partner and can include allosteric effects.
- an "antagonist” is a substance that inhibits its binding partner, typically a receptor. Inhibition is defined in the context of the particular assay, or may be apparent in the literature from a discussion herein that makes a comparison to a factor or substance that is accepted as an "agonist” or an “antagonist” of the particular binding partner under substantially similar circumstances as appreciated by those of skill in the art. Inhibition may be defined with respect to a decrease in a particular effect or function that is induced by interaction of the antagonist with a binding partner, and can include allosteric effects.
- a "partial agonist” is a substance that provides a level of stimulation to its binding partner that is intermediate between that of a full or complete antagonist and an agonist defined by any accepted standard for agonist activity. It will be recognized that stimulation, and hence, inhibition is defined intrinsically for any substance or category of substances to be defined as agonists, antagonists, or partial agonists.
- "intrinsic activity”, or “efficacy” relates to some measure of biological effectiveness of the binding partner complex. With regard to receptor pharmacology, the context in which intrinsic activity or efficacy should be defined will depend on the context of the binding partner (e.g. receptor/ligand) complex and the consideration of an activity relevant to a particular biological outcome.
- intrinsic activity may vary depending on the particular second messenger system involved. See Hoyer and Boddeke, Trends Pharmacol ScL, 14(7): 270 (1993). Where such contextually specific evaluations are relevant, and how they might be relevant in the context of the present invention, will be apparent to one of ordinary skill in the art.
- Cy is 3-pyridinyl or 5-pyrimidinyl, Y is oxygen, Z is a covalent bond and A is absent.
- Cy is 3-pyridinyl or 5- pyrimidinyl, Y is oxygen, Z is nitrogen and A is absent.
- Cy is 3-pyridinyl or 5-pyrimidinyl, Y is oxygen, Z is a covalent bond, and A is a linker species.
- Cy is 3-pyridinyl or 5-pyrimidinyl, Y is oxygen, Z is nitrogen and A is a linker species.
- Representative compounds of the present invention include: 5-benzoyl-3-pyridin-3-yl-l,5-diazatricyclo[5.2.2.0 ⁇ 2,6>3undecane, 5-(2-fluorobenzoyl)-3-pyridin-3-yl-l,5-diazatricyclo[5.2.2.0 ⁇ 2,6>]undecane, 5-(3-fluorobenzoyl)-3-pyridin-3-yl-l,5-diazatricyclo[5.2.2.0 ⁇ 2,6>]undecane, 5-(4-fluorobenzoyl)-3-pyridin-3-yl-l,5-diazatricyclo[5.2.2.0 ⁇ 2,6>]undecane, 5-(2-chlorobenzoyl)-3-pyridin-3-yl-l,5-diazatricyclo[5.2.2.0 ⁇ 2,6>]undecane, 5-(3-chlorobenzoyl)-3-pyridin-3-yl-l,5-di
- Other compounds representative of the present invention include: 5-(phenylacetyl)-3-pyridin-3-yl-l,5-diazatricyclo[5.2.2.0 ⁇ 2,6>]undecane, 5-(diphenylacetyl)-3-pyridin-3-yl-l,5-diazatricyclo[5.2.2.0 ⁇ 2,6>]undecane, 5-(2-phenylpropanoyl)-3-pyridin-3-yl-l,5-diazatricyclo[5.2.2.0 ⁇ 2,6>]undecane, and 5-(3-phenylprop-2-enoyl)-3-pyridin-3-yl-l,5-diazatricyclo[5.2.2.0 ⁇ 2,6>]undecane.
- a 3-pyridin-3-yl-l,5- diazatricyclo[5.2.2.0 ⁇ 2,6>]undecane moiety has the structure, with a partial numbering scheme provided, shown below:
- the nitrogen at the position indicated above as the 5-position is the nitrogen involved in the formation of the amides, thioamides, ureas and thioureas described herein.
- the manner in which compounds of the present invention can be prepared can vary. While other synthetic strategies will be apparent to those of skill in the art, the compounds of Formula 1 can be made by cyclization of aldol condensation products formed from heteroaromatic aldehydes and l-azabicyclo[2.2.2]octan-3-one. Thus, when 3-quinuclidinone hydrochloride is reacted with pyridine-3-carboxaldehyde (available from Aldrich Chemical Company), in the presence of methanolic potassium hydroxide, 2-((3-pyridinyl)methylene)-l-azabicyclo[2.2.2]octan-3-one results.
- pyridine-3-carboxaldehyde available from Aldrich Chemical Company
- heteroaromatic aldehydes can be used in the aldol condensation, in place of ⁇ yridine-3-carboxaldehyde (variation at Cy).
- Treatment of 2-((3- pyridinyl)methylene)-l-azabicyclo[2.2.2]octan-3-one with nitromethane and sodium methoxide results in conjugate addition of the nitromethane anion to the enone functionality.
- the nitro group, of 2-(l-(3-pyridinyl)-2-nitroethyl)-l- azabicyclo[2.2.2]octan-3-one is then reduced with Raney nickel to give the corresponding amine.
- reactive groups on Cy or AR may require protection.
- Methods described by Greene and Wuts, Protective Groups in Organic Synthesis 2 nd ed., Wiley - Interscience Pub. (1991) can be used to protect and deprotect these reactive groups.
- the compounds can be isolated and purified using methods well known to those of skill in the art, including, for example, crystallization, chromatography and/or extraction.
- the compounds of general Formula 1 can be obtained in optically pure form by separating their racemates in accordance with the customary methods.
- the compounds of general Formula 1 can optionally be converted into addition salts with a mineral or organic acid by the action of such an acid in an appropriate solvent, for example, an organic solvent such as an alcohol, a ketone, an ether or a chlorinated solvent.
- an appropriate solvent for example, an organic solvent such as an alcohol, a ketone, an ether or a chlorinated solvent.
- Representative pharmaceutically acceptable salts include, but are not limited to, benzenesulphonate, hydrobromide, hydrochloride, citrate, ethanesulphonate, fumarate, gluconate, iodate, maleate, isethionate, methanesulphonate, methylenebis( ⁇ -oxynaphthoate), nitrate, oxalate, paknoate, phosphate, salicylate, succinate, sulphate, tartrate, theophyllinacetate, p-toluenesulphonate, hemigalactarate and galactarate salts.
- Certain compounds of. the present invention can be synthesized in such a manner as to incorporate a radionuclide useful in diagnostic imaging.
- a radionuclide useful in diagnostic imaging Of particular interest are those compounds that include radioactive isotopic moieties such as 11 C, 18 F, 76 Br, 123 1, 125 I, and the like.
- the compounds can be radiolabeled at any of a variety of positions.
- a radionuclide of the halogen series may be used within an alkyl halide or aryl halide moiety or functionality, while a radionuclide such as 11 C maybe used with an alkyl (e.g., methyl) moiety or functionality.
- Cy is as described above, and wherein the Cy and 1,5- diazatricyclo[5.2.2.0 ⁇ 2,6>]undecane ring can be functionalized with the various substituents described above, to form the desired p- 18 fluorobenzamide derivative, using any of a variety of techniques known to those skilled in the art (some of which are described previously).
- the resulting compound can be used to specifically image ⁇ 7 nAChRs.
- the related urea compound can be prepared by replacing the p- 18 fluorobenzoic acid with a compound that includes a 18 fluoroalkyl or 18 fluoroarylalkyl N-C(O)-O-alkyl or other activated group with the NH group at the 5- position of the starting material described above.
- the related thiourea or thioamide compounds can be prepared by replacing the p- 18 fluorobenzoic acid with ap- 18 fluorothiobenzoic acid, thiobenzoic acid or with a compound that includes an N- C(S)-O-alkyl or other activated group with the NH group at the 5-position of the starting material described above.
- This same starting material can be readily radiolabeled by reacting the amine group at the 5-position with an activating agent such as ethyl chloroformate to form an N-C(O)-ethoxy group (or other activated carbonyl compound), which in turn is reacted with a radiolabeled aryl or arylalkyl amine (i.e., to form aryl ureas or arylalkyl ureas, where the radiolabel is on the aryl or arylalkyl moiety).
- an activating agent such as ethyl chloroformate to form an N-C(O)-ethoxy group (or other activated carbonyl compound)
- a radiolabeled aryl or arylalkyl amine i.e., to form aryl ureas or arylalkyl ureas, where the radiolabel is on the aryl or arylalkyl moiety.
- a radiolabeled aryl or arylalkyl isocyanate can be reacted with the amine at the 5-position to form a radiolabeled urea group.
- bromophenyl-p-isocyanate carbonyl 14 C
- the resulting radiolabeled compounds can be purified by semi-preparative or preparative HPLC and briefly isolated for reconstitution.
- the required amine-containing precursor compounds are described in detail above, and the resulting radiolabeled compounds can be used to specifically image ⁇ 7 nAChRs.
- the compounds described herein can be incorporated into pharmaceutical compositions and used to prevent a condition or disorder in a subject susceptible to such a condition or disorder, and/or to treat a subject suffering from the condition or disorder.
- the pharmaceutical compositions described herein include one or more compounds of Formula 1 and/or pharmaceutically acceptable salts thereof. Chiral compounds can be employed as racemic mixtures or as pure enantiomers.
- compositions are preferably administered orally (e.g., in liquid form within a solvent such as an aqueous or non-aqueous liquid, or within a solid carrier).
- Preferred compositions for oral administration include pills, tablets, capsules, caplets, syrups, and solutions, including hard gelatin capsules and time-release capsules.
- Compositions can be formulated in unit dose form, or in multiple or subunit doses.
- Preferred compositions are in liquid or semisolid form.
- Compositions including a liquid pharmaceutically inert carrier such as water or other pharmaceutically compatible liquids or semisolids can be used. The use of such liquids and semisolids is well known to those of skill in the art.
- compositions can also be administered via injection, i.e., intravenously, intramuscularly, subcutaneously, intraperitoneally, intraarterially, intrathecally; and intracerebroventricularly.
- Intravenous administration is the preferred method of injection.
- Suitable carriers for injection are well known to those of skill in the art and include 5% dextrose solutions, saline, and phosphate-buffered saline.
- the compounds can also be administered as an infusion or injection (e.g., as a suspension or as an emulsion in a pharmaceutically acceptable liquid or mixture of liquids).
- the formulations can also be administered using other means, for example, rectal administration.
- Formulations useful for rectal administration such as suppositories, are well known to those of skill in the art.
- the compounds can also be administered by inhalation (e.g., in the form of an aerosol either nasally or using delivery articles of the type set forth in U.S. Patent No. 4,922,901 to Brooks et al., the disclosure of which is incorporated herein in its entirety); topically (e.g., in lotion form); or transdermally (e.g., using a transdermal patch, using technology that is commercially available from Novartis and Alza Corporation).
- inhalation e.g., in the form of an aerosol either nasally or using delivery articles of the type set forth in U.S. Patent No. 4,922,901 to Brooks et al., the disclosure of which is incorporated herein in its entirety
- topically e.g., in lotion form
- transdermally e.g., using
- compositions used and the particular subject receiving the treatment can contain a liquid carrier that can be oily, aqueous, emulsified or contain certain solvents suitable to the mode of administration.
- compositions can be administered intermittently or at a gradual, continuous, constant or controlled rate to a warm-blooded animal (e.g., a mammal such as a mouse, rat, cat, rabbit, dog, pig, cow, or monkey), but advantageously are administered to a human being.
- a warm-blooded animal e.g., a mammal such as a mouse, rat, cat, rabbit, dog, pig, cow, or monkey
- time of day and the number of times per day that the pharmaceutical formulation is administered can vary.
- the active ingredients interact with receptor sites within the body of the subject that affect the functioning of the CNS. More specifically, in treating a CNS disorder, preferable administration is designed to optimize the effect upon those relevant nicotinic acetylcholine receptor (nAChR) subtypes that have an effect upon the functioning of the CNS, while minimizing the effects upon muscle-type receptor subtypes.
- nAChR nicotinic acetylcholine receptor
- Other suitable methods for administering the compounds of the present invention are described in U.S. Patent No. 5,604,231 to Smith et al., the contents of which are hereby incorporated by reference.
- the compounds described herein can be employed as part of a pharmaceutical composition with other compounds intended to prevent or treat a particular disorder.
- the pharmaceutical compositions can also include various other components as additives or adjuncts.
- exemplary pharmaceutically acceptable components or adjuncts which are employed in relevant circumstances include antioxidants, free-radical scavenging agents, peptides, growth factors, antibiotics, bacteriostatic agents, immunosuppressives, anticoagulants, buffering agents, antiinflammatory agents, anti-pyretics, time-release binders, anesthetics, steroids, vitamins, minerals and corticosteroids.
- Such components can provide additional therapeutic benefit, act to affect the therapeutic action of the pharmaceutical composition, or act towards preventing any potential side effects that can be imposed as a result of administration of the pharmaceutical composition.
- the appropriate dose of the compound is that amount effective to prevent occurrence of the symptoms of the disorder or to treat some symptoms of the disorder from which the patient suffers.
- effective amount By “effective amount”, “therapeutic amount” or “effective dose” is meant that amount sufficient to elicit the desired pharmacological or therapeutic effects, thus resulting in effective prevention or treatment of the disorder.
- an effective amount of compound is an amount sufficient to pass across the blood-brain barrier of the subject, to bind to relevant receptor sites in the brain of the subject and to modulate the activity of relevant nAChR subtypes (e.g., provide neurotransmitter secretion, thus resulting in effective prevention or treatment of the disorder).
- Prevention of the disorder is manifested by delaying the onset of the symptoms of the disorder.
- Treatment of the disorder is manifested by a decrease in the symptoms associated with the disorder or an amelioration of the recurrence of the symptoms of the disorder.
- the effective amount is sufficient to obtain the desired result, but insufficient to cause appreciable side effects.
- the effective dose can vary, depending upon factors such as the condition of the patient, the severity of the symptoms of the disorder, and the manner in which the pharmaceutical composition is administered.
- the effective dose of typical compounds generally requires administering the compound in an amount sufficient to modulate the activity of relevant nAChRs to effect neurotransmitter (e.g., dopamine) release, but the amount should be insufficient to induce effects on skeletal muscles and ganglia to any significant degree.
- the effective dose of compounds will of course differ from patient to patient, but in general includes amounts starting where CNS effects or other desired therapeutic effects occur but below the amount where muscular effects are observed.
- the compounds when employed in effective amounts in accordance with the method described herein, are selective to certain relevant nAChRs, but do not significantly activate receptors associated with undesirable side effects at concentrations at least greater than those required for eliciting the release of dopamine or other neurotransmitters.
- a particular dose of compound effective in preventing and/or treating a CNS disorder is essentially ineffective in eliciting activation of certain ganglionic-type nAChRs at concentration higher than 5 times, preferably higher than 100 times, and more preferably higher than 1,000 times than those required for modulation of neurotransmitter release.
- the compounds described herein when employed in effective amounts in accordance with the methods described herein, can provide some degree of prevention of the progression of CNS disorders, ameliorate symptoms of CNS disorders, and ameliorate to some degree of the recurrence of CNS disorders.
- the effective amounts of those compounds are typically below the threshold concentration required to elicit any appreciable side effects, for example those effects relating to skeletal muscle.
- the compounds can be administered in a therapeutic window in which certain CNS disorders are treated and certain side effects are avoided.
- the effective dose of the compounds described herein is sufficient to provide the desired effects upon the CNS but is insufficient (i.e., is not at a high enough level) to provide undesirable side effects.
- the compounds are administered at a dosage effective for treating the CNS disorders but less than 1/5, and often less than 1/10, the amount required to elicit certain side effects to any significant degree.
- effective doses are at very low concentrations, where maximal effects are observed to occur, with a minimum of side effects.
- the effective dose of such compounds generally requires administering the compound in an amount of less than 5 mg/kg of patient weight.
- the compounds of the present invention are administered in an amount from less than about 1 mg/kg patent weight and usually less than about 100 ⁇ g/kg of patient weight, but frequently between about 10 ⁇ g to less than 100 ⁇ g/kg of patient weight.
- the effective dose is less than 5 mg/kg of patient weight; and often such compounds are administered in an amount from 50 ⁇ g to less than 5 mg/kg of patient weight.
- the foregoing effective doses typically represent that amount administered as a single dose, or as one or more doses administered over a 24-hour period.
- the effective dose of typical compounds generally requires administering the compound in an amount of at least about 1, often at least about 10, and frequently at least about 100 mg/ 24 hr/ patient.
- the effective dose of typical compounds requires administering the compound which generally does not exceed about 500, often does not exceed about 400, and frequently does not exceed about 300 mg/ 24 hr/ patient.
- the compositions are advantageously administered at an effective dose such that the concentration of the compound within the plasma of the patient normally does not exceed 50 ng/mL, often does not exceed 30 ng/mL, and frequently does not exceed 10 ng/mL.
- the compounds can be used to treat those types of conditions and disorders for which other types of nicotinic compounds have been proposed as therapeutics. See, for example, Williams et al., Drug News Perspec. 7(4): 205 (1994); Arneric et al., CNS Drug Rev. 1(1): 1 (1995); Arneric et al., Exp. Opin. Invest. Drugs 5(1): 79 (1996); Bencherif et al., J Pharmacol. Exp. Then 279: 1413 (1996); Lippiello et al., J Pharmacol. Exp. Ther. 279: 1422 (1996); Damaj et al., J Pharmacol. Exp. Ther.
- the compounds can be used to treat those types of conditions and disorders for which nicotinic compounds with selectivity for the ⁇ 7 nAChR subtype have been proposed as therapeutics. See, for example, Leonard et al., Schizophrenia Bulletin 22(3): 431 (1996); Freedman et al., Biological Psychiatry 38(1): 22 (1995); Heeschen et al., J. Clin. Invest. 100: 527 (2002); Utsugisawa et al., Molecular Brain Research 106(1-2): 88 (2002); U.S.
- the compounds can also be used as adjunct therapy in combination with existing therapies in the management of the aforementioned types of diseases and disorders.
- it is preferably to administer the active ingredients in a manner that minimizes effects upon nAChR subtypes such as those that are associated with muscle and ganglia. This can be accomplished by targeted drug delivery and/or by adjusting the dosage such that a desired effect is obtained without meeting the threshold dosage required to achieve significant side effects.
- the pharmaceutical compositions can be used to ameliorate any of the symptoms associated with those conditions, diseases and disorders. Representative classes of disorders that can be treated are discussed in detail below.
- CNS disorders can be drug induced; can be attributed to genetic predisposition, infection or trauma; or can be of unknown etiology.
- CNS disorders comprise neuropsychiatric disorders, neurological diseases and mental illnesses, and include neurodegenerative diseases, behavioral disorders, cognitive disorders and cognitive affective disorders.
- CNS disorders whose clinical manifestations have been attributed to CNS dysfunction (i.e., disorders resulting from inappropriate levels of neurotransmitter release, inappropriate properties of neurotransmitter receptors, and/or inappropriate interaction between neurotransmitters and neurotransmitter receptors).
- CNS disorders can be attributed to a deficiency of choline, dopamine, norepinephrine and/or serotonin.
- CNS disorders examples include pre-senile dementia (early onset Alzheimer's disease), senile dementia (dementia of the Alzheimer's type), Lewy Body dementia, micro-infarct dementia, AIDS-related dementia, HTV-dementia, multiple cerebral infarcts, Parkinsonism including Parkinson's disease, Pick's disease, progressive supranuclear palsy, Huntington's chorea, tardive dyskinesia, hyperkinesia, mania, attention deficit disorder, anxiety, depression, dyslexia, schizophrenia, obsessive-compulsive disorders, Tourette's syndrome, mild cognitive impairment (MCI), age-associated memory impairment (AAMT), premature amnesic and cognitive disorders which are age-related or a consequence of alcoholism, or immunodeficiency syndrome, or are associated with vascular disorders, with genetic alterations (such as, for example, trisomy 21) or with attention deficiencies or learning deficiencies, acute or chronic neurodegenerative conditions such as amyo
- Schizophrenia is an example of a CNS disorder that is particularly amenable to treatment by modulating the ⁇ 7 nAChR subtype.
- the compounds can also be administered to improve cognition and/or provide neuroprotection, and these uses are also particularly amenable to treatment with compounds, such as the compounds of the present invention, that are specific for the ⁇ 7 nAChR subtype.
- the disorders can be treated and/or prevented by administering to a patient in need of treatment or prevention thereof an effective treatment or preventative amount W of a compound that provides some degree of prevention of the progression of a CNS disorder (i.e., provides protective effects), ameliorating the symptoms of the disorder, and ameliorating the recurrence of the disorder.
- TNF tumor necrosis factor
- diseases include, but are not limited to, endotoxemia, sepsis, rheumatoid arthritis, and irritable bowel disease.
- the nervous system primarily through the vagus nerve, is known to regulate the magnitude of the innate immune response by inhibiting the release of macrophage tumor necrosis factor. This physiological mechanism is known as the "cholinergic anti-inflammatory pathway" (see, for example, Tracey, Nature. 420(6917): 853 (2002)).
- nAChR ⁇ 7 subunit is required for acetylcholine inhibition of macrophage TNF release, and also inhibits release of other cytokines.
- Agonists (or, at elevated dosages, partial agonists) at the ⁇ 7-specific nAChR subtype can inhibit the TNF- modulated inflammatory response. Accordingly, those compounds described herein that are oc7 agonists can be used to treat inflammatory disorders characterized by excessive synthesis of TNF (see also Wang et al., Nature, 421(6921): 384 (2003)).
- Inflammatory conditions that can be treated or prevented by administering the compounds described herein include, but are not limited to chronic and acute inflammation, psoriasis, gout, acute pseudogout, acute gouty arthritis, arthritis, rheumatoid arthritis, osteoarthritis, allograft rejection, chronic transplant rejection, asthma, atherosclerosis, mononuclear-phagocyte dependent lung injury, idiopathic pulmonary fibrosis, atopic dermatitis, chronic obstructive pulmonary disease, adult respiratory distress syndrome, acute chest syndrome in sickle cell disease, inflammatory bowel disease, Crohn's disease, ulcerative colitis, acute cholangitis, aphteous stomatitis, glomerulonephritis, lupus nephritis, thrombosis, and graft vs. host reaction.
- bacterial and/or viral infections are associated with side effects brought on by the formation of toxins, and the body's natural response to the bacteria or virus and/or the toxins. Examples of such bacterial infections include anthrax, botulism, and sepsis. As discussed above, the body's response to infection often involves generating a significant amount of tumor necrosis factor and/or other cytokines. The over-expression of these cytokines can result in significant injury, such as septic shock (when the bacteria is sepsis), endotoxic shock, urosepsis and toxic shock syndrome.
- Cytokine expression is mediated by the oc7 nAChR and can be inhibited by administering agonists or partial agonists of these receptors.
- Those compounds described herein that are agonists or partial agonists of these receptors can therefore be used to minimize the inflammatory response associated with bacterial infection, as well as viral and fungal infections. Certain of the compounds themselves may also have antimicrobial properties.
- Antitoxins can also be used to bind to toxins produced by the infectious agents and allow the bound toxins to pass through the body without generating an inflammatory response. Examples of antitoxins are disclosed, for example, in U.S. Patent No. 6,310,043 to Bundle et al., incorporated herein by reference. Other agents effective against bacterial and other toxins can be effective and their therapeutic effect can be complimented by co-administration with the compounds described herein.
- the compounds can be administered to treat and/or prevent pain, including neurologic, neuropathic and chronic pain.
- the analgesic activity of compounds described herein can be demonstrated in models of persistent inflammatory pain and of neuropathic pain, performed as described in U.S. Published Patent Application No. 20010056084 Al to Allgeier et al. (e.g., mechanical hyperalgesia in the complete Freund's adjuvant rat model of inflammatory pain and mechanical hyperalgesia in the mouse partial sciatic nerve ligation model of neuropathic pain).
- the analgesic effect is suitable for treating pain of various genesis or etiologies, in particular in treating inflammatory pain and associated hyperalgesia, neuropathic pain and associated hyperalgesia, chronic pain (e.g., severe chronic pain, post-operative pain and pain associated with various conditions including cancer, angina, renal or biliary colic, menstruation, migraine and gout) and fibromyalgia syndrome.
- Inflammatory pain may be of diverse genesis, including arthritis and rheumatoid disease, teno-synovitis and vasculitis.
- Neuropathic pain includes trigeminal or herpetic neuralgia, diabetic neuropathy pain, causalgia, low back pain and deafferentation syndromes such as brachial plexus avulsion.
- the ⁇ 7 nAChR is also associated with neovascularization.
- Inhibition of neovascularization for example, by administering antagonists (or at certain dosages, partial agonists) of the ⁇ 7 nAChR can inhibit neovascularization and, accordingly, treat or prevent conditions characterized by undesirable neovascularization or angiogenesis.
- Such conditions can include those characterized by inflammatory angiogenesis and/or ischemia-induced angiogenesis.
- Neovascularization associated with tumor growth can also be inhibited by administering those compounds described herein that function as antagonists or partial agonists of ⁇ 7 nAChR.
- Representative tumor types that can be treated using the compounds described herein include NSCLC, ovarian cancer, pancreatic cancer, breast carcinoma, colon carcinoma, rectum carcinoma, lung carcinoma, oropharynx carcinoma, hypopharynx carcinoma, esophagus carcinoma, stomach carcinoma, pancreas carcinoma, liver carcinoma, gallbladder carcinoma, bile duct carcinoma, small intestine carcinoma, urinary tract carcinoma, kidney carcinoma, bladder carcinoma, urothelium carcinoma, female genital tract carcinoma, cervix carcinoma, uterus carcinoma, ovarian carcinoma, cnonocarcinoma, gestational trophoblastic disease, male genital tract carcinoma, prostate carcinoma, seminal vesicles carcinoma, testes carcinoma, germ cell tumors, endocrine gland carcinoma, thyroid carcinoma, adrenal carcinoma, pituitary gland carcinoma, skin carcinoma, hemangiomas, melanomas, sarcomas, bone and soft tissue sarcoma, Kaposi's sarcoma, tumors of the brain, tumor
- the compounds can also be administered in conjunction with other forms of anti-cancer treatment, including co-administration with antineoplastic antitumor agents such as cis-platin, adriamycin, daunomycin, and the like, and/or anti-VEGF vascular endothelial growth factor) agents, as such are known in the art.
- antineoplastic antitumor agents such as cis-platin, adriamycin, daunomycin, and the like
- anti-VEGF vascular endothelial growth factor anti-VEGF vascular endothelial growth factor
- the compounds can be administered in such a manner that they are targeted to he tumor site.
- the compounds can be administered in microspheres, nicroparticles or liposomes conjugated to various antibodies that direct the nicroparticles to the tumor.
- the compounds can be present in microspheres, microparticles or liposomes that are appropriately sized to pass through tie arteries and veins, but lodge in capillary beds surrounding tumors and administer ie compounds locally to the tumor.
- Such drug delivery devices are known in the art.
- the compounds can be also used to prevent r treat certain other conditions, diseases, and disorders.
- itoimmune disorders such as Lupus, disorders associated with cytokine release, ichexia secondary to infection (e.g., as occurs in AE)S, AIDS related complex and joplasia), as well as those indications set forth in PCT WO 98/25619.
- the impounds can also be administered to treat convulsions such as those that are mptomatic of epilepsy, and to treat conditions such as syphilis and Creutzfeldt- kob disease. Diagnostic Uses
- the compounds can be used in diagnostic compositions, such as probes, particularly when they are modified to include appropriate labels.
- the probes can be used, for example, to determine the relative number and/or function of specific receptors, particularly the ⁇ 7 receptor subtype.
- the compounds of the present invention most preferably are labeled with a radioactive iso topic moiety such as 11 C, 18 F, 76 Br, 123 I or 125 I, as discussed above.
- the administered compounds can be detected using known detection methods appropriate for the label used. Examples of detection methods include position emission topography (PET) and single-photon emission computed tomography
- SPECT single photoelectron emission tomography
- the radiolabels described above are useful in PET (e.g., 11 C, 18 F or 76 Br) ind SPECT (e.g., 123 I) imaging, with half-lives of about 20.4 minutes for 11 C, about
- a high pecific activity is desired to visualize the selected receptor subtypes at non-saturating oncentrations.
- the administered doses typically are below the toxic range and irovide high contrast images.
- the compounds are expected to be capable of dministration in non-toxic levels. Determination of dose is carried out in a manner nown to one skilled in the art of radiolabel imaging. See, for example, U.S. Patent
- the compounds can be administered using known techniques. See, for sample, U.S. Patent No. 5,969,144 to London et al.
- the compounds can be lministered in formulation compositions that incorporate other ingredients, such as Lose types of ingredients that are useful in formulating a diagnostic composition, ompounds useful in accordance with carrying out the present invention most eferably are employed in forms of high purity. See, for example, U.S. Patent No. 853,696 to Elmalch et al.
- the esence of that compound within the subject can be imaged and quantified by muscularte techniques in order to indicate the presence, quantity, and functionality of lected nicotinic cholinergic receptor subtypes.
- the mpounds can also be administered to animals, such as mice, rats, dogs, and monkeys.
- SPECT and PET imaging can be carried out using any appropriate technique and apparatus. See Villemagne et al., In: Arneric et al., (Eds.) Neuronal Nicotinic Receptors: Pharmacology and Therapeutic Opportunities, 235-250 (1998) and U.S. Patent No. 5,853,696 to Elmalch et al. for a disclosure of representative imaging techniques.
- the radiolabeled compounds bind with high affinity to selective nAChR subtypes (e.g., ⁇ 7) and preferably exhibit negligible non-specific binding to other nicotinic cholinergic receptor subtypes (e.g., those receptor subtypes associated with muscle and ganglia).
- nAChR subtypes e.g., ⁇ 7
- nicotinic cholinergic receptor subtypes e.g., those receptor subtypes associated with muscle and ganglia.
- the compounds can be used as agents for noninvasive imaging of nAChR subtypes within the body of a subject, particularly within the brain for diagnosis associated with a variety of CNS diseases and disorders.
- the diagnostic compositions can be used in a method to diagnose disease in a subject, such as a human patient.
- the method involves administering to that patient a detectably labeled compound as described herein, and detecting the binding of that compound to selected nicotinic receptor subtypes (e.g., ⁇ 7 receptor subtype).
- selected nicotinic receptor subtypes e.g., ⁇ 7 receptor subtype.
- diagnostic tools such as PET and SPECT
- Such disorders include a wide variety of CNS diseases and disorders, including Alzheimer's disease, Parkinson's disease, and schizophrenia.
- CNS diseases and disorders including Alzheimer's disease, Parkinson's disease, and schizophrenia.
- the diagnostic compositions can be used in a method to monitor selective nAChR subtypes of a subject, such as a human patient.
- the method involves administering a detectably labeled compound as described herein to that patient and detecting the binding of that compound to selected nAChR subtypes (e.g., the ⁇ 7 receptor subtype).
- Example 1 Amide derivatives of 3-pyridin-3-yI-l,5- diazatricyclo [5.2.2.0 ⁇ 2,6>] undecane
- Benzotriazol- 1 -yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP, 0.097 g, 0.22 mmol) was added to a solution of the carboxylic acid (0.22 mmol) and triethylamine (0.66 mmol) in dichloromethane (1 mL), and then 3-pyridin- 3-yl-l,5-diazatricyclo[5.2.2.0 ⁇ 2,6>]undecane (0.046 g, 0.20 mmol) was added. The mixture was stirred for 48 h at room temperature, then treated with 10% NaOH (0.2 mL).
- the biphasic mixture was separated by phase filtration, and the organic phase was concentrated on the Genevac centrifugal evaporator.
- the crude residue was dissolved in methanol (1 mL) and purified by HPLC on a Cl 8 silica gel column, using acetonitrile/water gradient containing 0.05% trifluoroacetic acid.
- Rats female, Sprague-Dawley, weighing 150-250 g, were maintained on a 12 light/dark cycle and were allowed free access to water and food supplied by PMI
- Drtex was removed and placed in 20 volumes (weight: volume) of ice-cold reparative buffer (137 mM NaCl, 10.7 mM KCl, 5.8 mM KH 2 PO 4 , 8 mM Na 2 HPO 4 ,
- the binding of [ 3 H]nicotine was measured using a modification of the methods of Romano et al., Science 210: 647 (1980) and Marks et al., MoI. Pharmacol. 30: 427 (1986).
- the binding of [ 3 H]nicotine was measured using a 3 h incubation at 4°C. Incubations were conducted in 48-well micro-titre plates and contained about 400 ⁇ g of protein per well in a final incubation volume of 300 ⁇ L.
- the incubation buffer was PBS and the final concentration of [ 3 H]nicotine was 5 nM.
- the binding reaction was terminated by filtration of the protein containing bound ligand onto glass fiber filters (GF/B, Brandel) using a Brandel Tissue Harvester at 4°C. Filters were soaked in de-ionized water containing 0.33 % polyethyleneimine to reduce non-specific binding. Each filter was washed with ice-cold buffer (3 x 1 mL). Non-specific binding was determined by inclusion of 10 ⁇ M non-radioactive L- nicotine (Acros Organics) in selected wells.
- IC 5O values were estimated as the :oncentration of compound that inhibited 50 percent of specific [ 3 H]nicotine binding, [nhibition constants (Ki values), reported in nM, were calculated from the IC 50 values ising the method of Cheng et al., Biochem. Pharmacol. 22: 3099 (1973).
- the binding reaction yas terminated by filtration of the protein containing bound ligand onto the glass fiber filter base of the Multiscreen plates. Filters were soaked in de-ionized water containing 0.33 % polyethyleneimine to reduce non-specific binding. Each filter was washed with ice-cold buffer (3 x 0.25 mL). Non-specific binding was determined by inclusion of 10 ⁇ M non-radioactive L-nicotine (Acros Organics) in selected wells. The single concentration of test compound was 5 ⁇ M and testing was performed in triplicate. 'Active' compounds were defined as compounds that inhibited the binding of [ 3 H]epibatidine to the receptor by at least 50% compared with the binding of [ 3 H]epibatidine in the absence of competitor. For those compounds found to be active in the single point screen, the inhibition constants (Ki values) were determined as described in the previous paragraphs of this section.
- Rats female, Sprague-Dawley
- Rats weighing 150-250 g
- Animals were anesthetized with 70% CO 2 , then decapitated. Brains were removed and placed on an ice-cold platform.
- the hippocampus was removed and placed in 10 volumes (weight: volume) of ice-cold preparative buffer (137 mM NaCl, 10.7 mM KCl, 5.8 mM KH 2 PO 4 , 8 mM Na 2 HPO 4 , 20 mM HEPES (free acid), 5 mM iodoacetamide, 1.6 mM EDTA, pH 7.4); PMSF, dissolved in methanol to a final concentration of 100 ⁇ M, was added and the tissue suspension was homogenized by Polytron. The homogenate was centrifuged at 18,000 x g for 20 min at 4 0 C and the resulting pellet was re-suspended in 10 volumes of ice-cold water.
- ice-cold preparative buffer 137 mM NaCl, 10.7 mM KCl, 5.8 mM KH 2 PO 4 , 8 mM Na 2 HPO 4 , 20 mM HEPES (free acid), 5 mM i
- Protein was ietermined by the method of Lowry et al., J. Biol. Client. 193: 265 (1951), using jovine serum albumin as the standard.
- the binding of [ 3 H]MLA was measured using a modification of the methods of Davies et al., Neuropharmacol. 38: 679 (1999).
- the binding of [ 3 H]MLA was determined using a 2 h incubation at 21 0 C. Incubations were conducted in 48-well micro-titre plates and contained about 200 ⁇ g of protein per well in a final incubation volume of 300 ⁇ L.
- the incubation buffer was PBS and the final concentration of [ 3 H]MLA was 5 nM.
- the binding reaction was terminated by filtration of the protein containing bound ligand onto glass fiber filters (GFfB, Brandel) using a Brandel Tissue Harvester at room temperature. Filters were soaked in de-ionized water containing 0.33 % polyethyleneimine to reduce non-specific binding. Each filter was washed with PBS (3 x 1 mL) at room temperature. Non-specific binding was determined by inclusion of 50 ⁇ M non-radioactive MLA in selected wells.
- IC 50 values were estimated as the concentration of compound that inhibited 50 percent of specific [ 3 H]MLA binding. Inhibition constants (Ki values), reported in nM, were calculated from the IC 50 values using the method of Cheng et al., Biochem. Pharmacol. 22: 3099 (1973).
- test compounds were tested in the above assay format with the following modifications. Incubations were conducted in 96-well plates in a final incubation volume of 150 ⁇ L. Once the binding reaction was terminated by filtration onto glass fiber filters, the filters were washed four times with approximately 250 ⁇ L of PBS at room temperature. Non-specific binding was determined by inclusion of 10 ⁇ M non-radioactive MLA in selected wells. The single concentration of test compound was 5 ⁇ M and testing was performed hi triplicate. 'Active' compounds were defined as compounds that inhibited the binding of [ 3 H]MLA to the receptor by at least 50% compared with the binding of [ 3 H]MLA in the absence of competitor. For those compounds found to be active in the single point screen, the inhibition constants (Ki values) were determined as described in the previous paragraphs of this section. Determination of Dopamine Release
- Dopamine release was measured using striatal synaptosomes obtained from rat brain, according to the procedures set forth by Rapier et al., J. Neurochem. 54: 937 (1990). Rats (female, Sprague-Dawley), weighing 150-250 g, were maintained on a 12 h light/dark cycle and were allowed free access to water and food supplied by PMI Nutrition International, Inc. Animals were anesthetized with 70% CO 2 , then decapitated. The brains were quickly removed and the striata dissected.
- Striatal tissue from each of 2 rats was pooled and homogenized in ice-cold 0.32 M sucrose (5 mL) containing 5 mM HEPES, pH 7.4, using a glass/glass homogenizer. The tissue was then centrifuged at 1,000 x g for 10 min. The pellet was discarded and the supernatant was centrifuged at 12,000 x g for 20 min.
- the resulting pellet was re-suspended in perfusion buffer containing monoamine oxidase inhibitors (128 mM NaCl, 1.2 mM KH 2 PO 4 , 2.4 mM KCl, 3.2 mM CaCl 2 , 1.2 mM MgSO 4 , 25 mM HEPES, 1 mM ascorbic acid, 0.02 mM pargyline HCl and 10 mM glucose, pH 7.4) and centrifuged for 15 min at 25,000 x g. The final pellet was resuspended in perfusion buffer (1.4 mL) for immediate use.
- monoamine oxidase inhibitors (128 mM NaCl, 1.2 mM KH 2 PO 4 , 2.4 mM KCl, 3.2 mM CaCl 2 , 1.2 mM MgSO 4 , 25 mM HEPES, 1 mM ascorbic acid, 0.02 mM pargyline HCl and 10 m
- Test compound (10 ⁇ M) or nicotine (10 ⁇ M) was then applied in the perfusion stream for 40 sec. Fractions (12 sec each) were continuously collected from each chamber throughout the experiment to capture basal release and agonist-induced peak release and to re-establish the baseline after the agonist application. The perfusate was collected directly into scintillation vials, to which scintillation fluid was added. [ 3 H]DA released was quantified by scintillation counting. For each chamber, the integrated area of the peak was normalized to its baseline.
- Release was expressed as a percentage of release obtained with an equal concentration of L-nicotine. Within each assay, each test compound was replicated using 2-3 chambers; replicates were averaged. When appropriate, dose-response curves of test compound were determined. The maximal activation for individual compounds (Emax) was determined as a percentage of the maximal activation induced by L-nicotine. The compound concentration resulting in half maximal activation (EC 50 ) of specific ion flux was also defined.
- nAChRs Activation of muscle-type nAChRs was established on the human clonal line TE671/RD, which is derived from an embryonal rhabdomyosarcoma (Stratton et al., Carcinogen 10: 899 (1989)). These cells express receptors that have pharmacological (Lukas, J. Pharmacol. Exp. Ther. 251: 175 (1989)), electrophysiological (Oswald et al., Neurosci. Lett. 96: 207 (1989)), and molecular biological profiles (Luther et al., J. Neurosci. 9: 1082 (1989)) similar to the muscle-type nAChR.
- TE671/RD cells were maintained in proliferative growth phase according to • outine protocols (Bencherif et al., MoI. Cell. Neurosci. 2: 52 (1991) and Bencherif et ⁇ l., J. Pharmacol. Exp. Ther. 257: 946 (1991)).
- Cells were cultured in Dulbecco's nodified Eagle's medium (Gibco/BRL) with 10% horse serum (Gibco/BRL), 5% fetal )ovine serum (HyClone, Logan UT), ImM sodium pyruvate, 4 mM L-Glutamine, and !O 5 OOO units penicillin-streptomycin (Irvine Scientific). When cells were 80% onfluent, they were plated to 6 well polystyrene plates (Costar). Experiments were onducted when the cells reached 100% confluency.
- Nicotinic acetylcholine receptor (nAChR) function was assayed using 86 Rb + fflux according to the method described by Lukas et al., Anal. Biochem. 175: 212 1988). On the day of the experiment, growth media was gently removed from the fell and growth media containing 86 Rubidium chloride (10 6 ⁇ Ci/mL) was added to ach well. Cells were incubated at 37°C for a minimum of 3 h.
- each point had 2 replicates, which were averaged.
- the amount Of 86 Rb + release was compared to both a positive control (100 ⁇ M L-nicotine) and a negative control (buffer alone) to determine the percent release relative to that of L-nicotine.
- rat ganglion nAChRs Activation of rat ganglion nAChRs was established on the pheochromocytoma clonal line PC 12, which is a continuous clonal cell line of neural crest origin, derived from a tumor of the rat adrenal medulla. These cells express ganglion-like nAChRs (see Whiting et al., Nature 327: 515 (1987); Lukas, J Pharmacol. Exp. Ther. 251: 175 (1989); Whiting et al., MoI. Brain Res. 10: 61 (1990)).
- Rat PC 12 cells were maintained in proliferative growth phase according to routine protocols (Bencherif et al., MoI. Cell. Neurosci. 2: 52 (1991) and Bencherif et al., J. Pharmacol. Exp. Ther. 257: 946 (1991)).
- Cells were cultured in Dulbecco's modified Eagle's medium (Gibco/BRL) with 10% horse serum (Gibco/BRL), 5% fetal bovine serum (HyClone, Logan UT), ImM sodium pyruvate, 4 mM L-Glutamine, and 50,000 units penicillin-streptomycin (Irvine Scientific).
- Nicotinic acetylcholine receptor (nAChR) function was assayed using 86 Rb + efflux according to a method described by Lukas et al., Anal. Biochem. 175: 212 (1988). On the day of the experiment, growth media was gently removed from the well and growth media containing 86 Rubidium chloride (10 6 ⁇ Ci/mL) was added to each well. Cells were incubated at 37°C for a minimum of 3 h.
- each point had 2 replicates, which were averaged.
- the amount of 86 Rb + release was compared to both a positive control (100 ⁇ M nicotine) and a negative control (buffer alone) to determine the percent release relative to that of L-nicotine.
- the cell line SH-SY5Y is a continuous line derived by sequential subcloning of the parental cell line, SK-N-SH, which was originally obtained from a human peripheral neuroblastoma.
- SH-SY5Y cells express a ganglion-like nAChR (Lukas et si., MoL Cell. Neurosci. 4: 1 (1993)).
- Nicotinic acetylcholine receptor (nAChR) function was assayed using 86 Rb + efflux according to a method described by Lukas et al., Anal. Biochem. 175: 212 (1988). On the day of the experiment, growth media was gently removed from the well and growth media containing 86 Rubidium chloride (10 6 ⁇ Ci/mL) was added to each well. Cells were incubated at 37 0 C for a minimum of 3 h.
- each point had 2 replicates, which were averaged.
- the amount of 86 Rb + release was compared to both a positive control (100 ⁇ M nicotine) and a negative control (buffer alone) to determine the percent release relative to that of L-nicotine.
- the human clonal line TE671/RD derived from an embryonal rhabdomyosarcoma (Stratton et al, Carcinogen 10: 899 (1989)), was used to define binding to the muscarinic M3 receptor subtype. As evidenced through pharmacological (Bencherif et al., J. Pharmacol. Exp. Ther. 257: 946 (1991) and Lukas, J. Pharmacol. Exp. Ther,. 251: 175 (1989)), electrophysiological (Oswald et al., Neurosci. Lett 96: 207 (1989)), and molecular biological studies (Luther et al., J Neurosci. 9: 1082 (1989)) these cells express muscle-like nicotinic receptors.
- TE671/RD cells were maintained in proliferative growth phase according to routine protocols (Bencherif et al., MoI. Cell. Neurosci. 2: 52 (1991) and Bencherif et al., J. Pharmacol. Exp. Ther. 257: 946 (1991)). They were grown to confluency on 20 - 150 mm tissue culture treated plates.
- the media was then removed and cells scraped using 80 mL of PBS (Dulbecco's Phosphate Buffered Saline, 138 mM NaCl, 2.67 mM KCl, 1.47 mM KH 2 PO 4 , 8.1 mM Na 2 HPO 4 , 0.9 mM CaCl 2 , 0.5 mM MgCl 2 , hivitrogen/Gibco, pH 7.4) and then centrifuged at 1000 rpm for 10 min. The supernatant was then suctioned off and the pellet(s) stored at -20 0 C until use.
- PBS Dynabecco's Phosphate Buffered Saline, 138 mM NaCl, 2.67 mM KCl, 1.47 mM KH 2 PO 4 , 8.1 mM Na 2 HPO 4 , 0.9 mM CaCl 2 , 0.5 mM MgCl 2 , hivitrogen/Gibco,
- the pellets were thawed, re-suspended with PBS and centrifuged at 18,000 x g for 20 min, then re-suspended in PBS to a final concentration of approximately 4 mg protein/mL and homogenized by Polytron. Protein was determined by the method of Lowry et al., J. Biol. Chem. 193: 265 (1951), using bovine serum albumin as the standard.
- [ 3 H]QNB The binding of [ 3 H]QNB was measured using a modification of the methods of Bencherif et al., J. Pharmacol. Exp. Ther. 257: 946 (1991).
- the binding of [ 3 H]QNB was measured using a 3 h incubation at 4 0 C. Incubations were conducted in 48-well micro-titre plates and contained about 400 ⁇ g of protein per well in a final incubation volume of 300 ⁇ L.
- the incubation buffer was PBS and the final concentration of [ 3 H]QNB was 1 nM.
- the binding reaction was terminated by filtration of the protein containing bound ligand onto glass fiber filters (GF/B, Brandel) using a Brandel Tissue Harvester at 4 0 C. Filters were pre-soaked in de- ionized water containing 0.33 % polyethyleneimine to reduce non-specific binding. Each filter was washed with ice-cold buffer (3 x 1 mL). Non-specific binding was determined by inclusion of 10 ⁇ M non-radioactive atropine in selected wells.
- the inhibition of [ 3 H]QNB binding by test compounds was determined by including seven different concentrations of the test compound in selected wells. Each concentration was replicated in triplicate. IC 5O values were estimated as the concentration of compound that inhibited 50 percent of specific [ 3 H]QNB binding. Inhibition constants (Ki values), reported in nM, were calculated from the IC 50 values using the method of Cheng et al., Biochem. Pharmacol. 22: 3099 (1973).
- Selective ⁇ 7 agonists can be found using a functional assay on FLIPR (see, for example, PCT WO 00/73431 A2, the contents of which are hereby incorporated by reference), which is a commercially available high throughput assay (Molecular Devices Corporation, Sunnyvale, California).
- FLIPR is designed to read the fluorescent signal from each well of a 96 or 384 well plate as fast as twice a second for up to 30 minutes. This assay can be used to accurately measure the functional pharmacology of cc7 nAChR and 5HT 3 R subtypes.
- Ki values at the ⁇ 7 subtype in the M-DM range indicating that they have very high affinity for the ⁇ 7 nAChR subtype
- E671/RD clonal cells E671/RD clonal cells
- ganglion-type receptors ⁇ 3 ⁇ 4 subtype in the Shooter ibclone of rat pheochromocytoma PC 12 cells and in human SHSY-5Y clonal cells
- 1-19% rat ganglion
- 1-15% human mglion
- compounds of the present invention are distinguished in their in vitro armacology from reference compounds (see, for instance, US Patent 5,712,270 to Sabb and PCTs WO 02/00652 and WO 02/051841) by virtue of the inclusion, in their structure, of the 3-pyridinylmethyl substituent in the 2 position of the 1-azabicycle.
- the compounds of the present invention are potent ⁇ 7 nicotinic ligands that selectively bind at oc7 nAChR subtypes.
- the compounds of the present invention do not bind well at those subtypes of the nAChR that are characteristic of the peripheral nervous system or at M3 muscarinic receptors.
- the compounds of the present invention possess therapeutic potential in treating central nervous system disorders without producing side effects associated with interaction with the peripheral nervous system.
- the affinity of these ligands for ⁇ 7 nAChR subtypes is tolerant of a wide variety of aryl (Ar in Formula 1) groups and substituents thereon. Furthermore, the synthesis is straightforward, efficient and amenable to massively parallel protocols.
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IL189204A IL189204A0 (en) | 2005-08-22 | 2008-02-03 | Heteroaryl-substituted diazatricycloalkanes, methods for its preparation and use thereof |
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Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008112734A1 (en) * | 2007-03-13 | 2008-09-18 | Targacept, Inc. | Heterocyclic-carbonyl-diazabicycloalkanes as modulators of the neuronal nicotinic acetylcholine alpha 4 beta 2, subtype receptor for the treatment of cns related disorders |
EP2409703A1 (en) | 2007-08-02 | 2012-01-25 | Targacept, Inc. | Treatment with alpha7-selective ligands |
JP2012508254A (en) * | 2008-11-11 | 2012-04-05 | ターガセプト,インコーポレイテッド | Treatment with α7 selective ligand |
US8476296B2 (en) | 2009-01-26 | 2013-07-02 | Targacept, Inc. | Preparation and therapeutic applications of (2S,3R)-N-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]OCT-3-yl)-3,5-difluorobenzamide |
WO2015191401A1 (en) * | 2014-06-13 | 2015-12-17 | Bristol-Myers Squibb Company | Tricyclic compounds as alpha- 7 nicotinic acetylcholine receptor ligands |
WO2017040778A1 (en) | 2015-09-04 | 2017-03-09 | Janssen Pharmaceutica Nv | Therapeutic compound for pain and synthesis thereof |
US11345681B1 (en) | 2020-06-05 | 2022-05-31 | Kinnate Biopharma Inc. | Inhibitors of fibroblast growth factor receptor kinases |
Families Citing this family (2)
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US20100179186A1 (en) * | 2008-10-10 | 2010-07-15 | University Of Kentucky Research Foundation | USE OF A NOVEL ALPHA-7 nAChR ANTAGONIST TO SUPPRESS PATHOGENIC SIGNAL TRANSDUCTION IN CANCER AND AIDS |
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Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004076449A2 (en) * | 2003-02-21 | 2004-09-10 | Targacept, Inc. | 3-substituted-2(arylalkyl)-1-azabicycloalkanes and methods of use thereof |
Family Cites Families (40)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1989000158A1 (en) | 1987-07-02 | 1989-01-12 | Pfizer Inc. | Bridged-diazabicycloalkyl quinolone carboxylic acids and esters |
US4922901A (en) | 1988-09-08 | 1990-05-08 | R. J. Reynolds Tobacco Company | Drug delivery articles utilizing electrical energy |
US5187166A (en) | 1990-07-31 | 1993-02-16 | Nisshin Flour Milling Co., Ltd. | Azabicyclo derivatives and their use as antiemetics |
WO1993009116A1 (en) * | 1991-11-07 | 1993-05-13 | Yoshitomi Pharmaceutical Industries, Ltd. | Quinuclidine compound and medicinal use thereof |
US5273972A (en) * | 1992-03-26 | 1993-12-28 | A. H. Robins Company, Incorporated | [(2-diakylaminomethyl)-3-quinuclidinyl]-benzamides and benzoates |
IL107184A (en) | 1992-10-09 | 1997-08-14 | Abbott Lab | Heterocyclic ether compounds that enhance cognitive function |
US5852041A (en) | 1993-04-07 | 1998-12-22 | Sibia Neurosciences, Inc. | Substituted pyridines useful as modulators of acethylcholine receptors |
US5493026A (en) | 1993-10-25 | 1996-02-20 | Organix, Inc. | Substituted 2-carboxyalkyl-3-(fluorophenyl)-8-(3-halopropen-2-yl) nortropanes and their use as imaging for agents for neurodegenerative disorders |
IT1274018B (en) | 1994-02-23 | 1997-07-14 | Riace Ets | 3,8-DIAZABICYCLE DERIVATIVES (3.2.1.) OCTANO FOR ANALGESIC ACTIVITY |
GB2295387A (en) | 1994-11-23 | 1996-05-29 | Glaxo Inc | Quinazoline antagonists of alpha 1c adrenergic receptors |
US5597919A (en) | 1995-01-06 | 1997-01-28 | Dull; Gary M. | Pyrimidinyl or Pyridinyl alkenyl amine compounds |
US5604231A (en) | 1995-01-06 | 1997-02-18 | Smith; Carr J. | Pharmaceutical compositions for prevention and treatment of ulcerative colitis |
US5585388A (en) | 1995-04-07 | 1996-12-17 | Sibia Neurosciences, Inc. | Substituted pyridines useful as modulators of acetylcholine receptors |
US5583140A (en) | 1995-05-17 | 1996-12-10 | Bencherif; Merouane | Pharmaceutical compositions for the treatment of central nervous system disorders |
IL118279A (en) | 1995-06-07 | 2006-10-05 | Abbott Lab | 3 - pyridyloxy (or thio) alkyl heterocyclic compounds, pharmaceutical compositions containing them and their uses in the preparation of medicaments for controlling chemical synaptic transmission |
US5712270A (en) | 1995-11-06 | 1998-01-27 | American Home Products Corporation | 2-arylamidothiazole derivatives with CNS activity |
US5616716A (en) | 1996-01-06 | 1997-04-01 | Dull; Gary M. | (3-(5-ethoxypyridin)yl)-alkenyl 1 amine compounds |
SE9600683D0 (en) | 1996-02-23 | 1996-02-23 | Astra Ab | Azabicyclic esters of carbamic acids useful in therapy |
AT403803B (en) | 1996-04-19 | 1998-05-25 | Sanochemia Ltd | NEW BENZAZEPINE DERIVATIVES, THESE MEDICINAL PRODUCTS AND THE USE THEREOF FOR THE PRODUCTION OF MEDICINAL PRODUCTS |
US5663356A (en) | 1996-04-23 | 1997-09-02 | Ruecroft; Graham | Method for preparation of aryl substituted alefinic secondary amino compounds |
US5726189A (en) | 1996-05-03 | 1998-03-10 | The United States Of America, Represented By The Secretary, Department Of Health And Human Services | Method for imaging nicotinic acetylcholinergic receptors in the brain using radiolabeled pyridyl-7-azabicyclo 2.2.1!heptanes |
ZA9711092B (en) | 1996-12-11 | 1999-07-22 | Smithkline Beecham Corp | Novel compounds. |
AR013184A1 (en) | 1997-07-18 | 2000-12-13 | Astrazeneca Ab | SPYROZOBICYCLIC HETERO CYCLIC AMINES, PHARMACEUTICAL COMPOSITION, USE OF SUCH AMINES TO PREPARE MEDICINES AND METHOD OF TREATMENT OR PROPHYLAXIS |
EP1491532B1 (en) | 1997-10-27 | 2010-12-15 | NeuroSearch A/S | Heteroaryl diazacycloalkanes as cholinergic ligands at nicotinic acetyloholine receptors |
US5952339A (en) | 1998-04-02 | 1999-09-14 | Bencherif; Merouane | Pharmaceutical compositions and methods of using nicotinic antagonists for treating a condition or disorder characterized by alteration in normal neurotransmitter release |
DE69913520T2 (en) | 1998-06-01 | 2004-11-25 | Ortho-Mcneil Pharmaceutical, Inc. | TETRAHYDRONAPHTALENE COMPOUNDS AND THE USE THEREOF FOR THE TREATMENT OF NEURODEGENERATIVE DISEASES |
US6310043B1 (en) | 1998-08-07 | 2001-10-30 | Governors Of The University Of Alberta | Treatment of bacterial infections |
GB9821503D0 (en) | 1998-10-02 | 1998-11-25 | Novartis Ag | Organic compounds |
US6734215B2 (en) | 1998-12-16 | 2004-05-11 | University Of South Florida | Exo-S-mecamylamine formulation and use in treatment |
JP2003501022A (en) | 1999-05-27 | 2003-01-14 | ファルマシア・アンド・アップジョン・カンパニー | Method for measuring ion channel conductance and composition thereof |
SE9904176D0 (en) | 1999-11-18 | 1999-11-18 | Astra Ab | New use |
AP1420A (en) | 2000-06-27 | 2005-05-30 | Salvat Lab Sa | Carbamates derived from arylalkylamines. |
US6479510B2 (en) | 2000-08-18 | 2002-11-12 | Pharmacia & Upjohn Company | Quinuclidine-substituted aryl compounds for treatment of disease |
WO2002016356A2 (en) | 2000-08-18 | 2002-02-28 | Pharmacia & Upjohn Company | Quinuclidine-substituted aryl moieties for treatment of disease (nicotinic acetylcholine receptor ligands) |
US6486172B2 (en) | 2000-08-18 | 2002-11-26 | Pharmacia & Upjohn Company | Quinuclidine-substituted aryl compounds for treatment of disease |
WO2002015662A2 (en) | 2000-08-21 | 2002-02-28 | Pharmacia & Upjohn Company | Quinuclidine-substituted heteroaryl moieties for treatment of disease (nicotinic acetylcholine receptor antagonists |
WO2002016355A2 (en) | 2000-08-21 | 2002-02-28 | Pharmacia & Upjohn Company | Quinuclidine-substituted heteroaryl moieties for treatment of disease (nicotinic) acetylcholine receptor ligands |
AU2001282875A1 (en) | 2000-08-21 | 2002-03-04 | Pharmacia And Upjohn Company | Quinuclidine-substituted heteroaryl moieties for treatment of disease |
SI1345937T1 (en) | 2000-12-22 | 2006-02-28 | Almirall Prodesfarma Ag | Quinuclidine carbamate derivatives and their use as m3 antagonists |
PE20021019A1 (en) * | 2001-04-19 | 2002-11-13 | Upjohn Co | SUBSTITUTED AZABYCLE GROUPS |
-
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Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2004076449A2 (en) * | 2003-02-21 | 2004-09-10 | Targacept, Inc. | 3-substituted-2(arylalkyl)-1-azabicycloalkanes and methods of use thereof |
Non-Patent Citations (2)
Title |
---|
DATABASE CAPLUS [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; BESIDSKY, YEVGENY ET AL: "Synthesis of perhydro-1,4-ethano-1,5-naphthyridine and perhydro-4,7-ethanopyrrolo[3,2-b]pyridine derivatives: potential NK1-receptor antagonists. X-ray molecular structures of (4aR*,8S*,8aR*)-6-oxo-8-phenylperhydro-1,4-ethano-1,5-naphthyridine and (4aR*,7R*,8R*,8aR*)-7,8-diphenylperhydro-1,4-ethano-", XP002412310, retrieved from STN Database accession no. 1995:396645 * |
JOURNAL OF THE CHEMICAL SOCIETY, PERKIN TRANSACTIONS 1: ORGANIC AND BIO-ORGANIC CHEMISTRY , (4), 465-74 CODEN: JCPRB4; ISSN: 0300-922X, 1995 * |
Cited By (26)
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WO2008112734A1 (en) * | 2007-03-13 | 2008-09-18 | Targacept, Inc. | Heterocyclic-carbonyl-diazabicycloalkanes as modulators of the neuronal nicotinic acetylcholine alpha 4 beta 2, subtype receptor for the treatment of cns related disorders |
EP2409703A1 (en) | 2007-08-02 | 2012-01-25 | Targacept, Inc. | Treatment with alpha7-selective ligands |
EP2484363A1 (en) | 2007-08-02 | 2012-08-08 | Targacept, Inc. | (2S,3R)-N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-5-methylthiophene-2-carboxamide |
JP2012508254A (en) * | 2008-11-11 | 2012-04-05 | ターガセプト,インコーポレイテッド | Treatment with α7 selective ligand |
JP2015028053A (en) * | 2008-11-11 | 2015-02-12 | ターガセプト,インコーポレイテッド | TREATMENT WITH α7 SELECTIVE LIGAND |
US8476296B2 (en) | 2009-01-26 | 2013-07-02 | Targacept, Inc. | Preparation and therapeutic applications of (2S,3R)-N-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]OCT-3-yl)-3,5-difluorobenzamide |
US8901151B2 (en) | 2009-01-26 | 2014-12-02 | Targacept, Inc. | Preparation and therapeutic applications of (2S, 3R)-N-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]OCT-3-yl)-3,5-difluorobenzamide |
US9173876B2 (en) | 2009-01-26 | 2015-11-03 | Targacept, Inc. | Preparation and therapeutic applications of (2S,3R)-N-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-3,5-difluorobenzamide |
WO2015191401A1 (en) * | 2014-06-13 | 2015-12-17 | Bristol-Myers Squibb Company | Tricyclic compounds as alpha- 7 nicotinic acetylcholine receptor ligands |
US9796713B2 (en) * | 2014-06-13 | 2017-10-24 | Bristol-Myers Squibb Company | Tricyclic compounds as alpha-7 nicotinic acetylcholine receptor ligands |
US20170129892A1 (en) * | 2014-06-13 | 2017-05-11 | Bristol-Myers Squibb Company | Tricyclic compounds as alpha-7 nicotinic acetylcholine receptor ligands |
WO2017040764A1 (en) | 2015-09-04 | 2017-03-09 | Janssen Pharmaceutica Nv | Therapeutic compounds for pain and synthesis thereof |
EP3344626A4 (en) * | 2015-09-04 | 2019-03-27 | Janssen Pharmaceutica N.V. | Therapeutic compounds for pain and synthesis thereof |
WO2017040772A1 (en) | 2015-09-04 | 2017-03-09 | Janssen Pharmaceutica Nv | Therapeutic compounds and synthesis |
WO2017040778A1 (en) | 2015-09-04 | 2017-03-09 | Janssen Pharmaceutica Nv | Therapeutic compound for pain and synthesis thereof |
CN108349934A (en) * | 2015-09-04 | 2018-07-31 | 詹森药业有限公司 | Therapeutic compound for pain and its synthesis |
CN108495854A (en) * | 2015-09-04 | 2018-09-04 | 詹森药业有限公司 | Therapeutic compound for pain and its synthesis |
EP3344614A4 (en) * | 2015-09-04 | 2019-03-27 | Janssen Pharmaceutica, N.V. | Therapeutic compounds for pain and synthesis thereof |
WO2017040770A1 (en) | 2015-09-04 | 2017-03-09 | Janssen Pharmaceutica Nv | Therapeutic compounds for pain and synthesis thereof |
EP3344629A4 (en) * | 2015-09-04 | 2019-03-27 | Janssen Pharmaceutica N.V. | Therapeutic compound for pain and synthesis thereof |
EP3344628A4 (en) * | 2015-09-04 | 2019-03-27 | Janssen Pharmaceutica, N.V. | Therapeutic compounds and synthesis |
EP3344627A4 (en) * | 2015-09-04 | 2019-03-27 | Janssen Pharmaceutica N.V. | Therapeutic compounds for pain and synthesis thereof |
US10766898B2 (en) | 2015-09-04 | 2020-09-08 | Janssen Pharmaceutica Nv | Therapeutic compound for pain and synthesis thereof |
CN108495854B (en) * | 2015-09-04 | 2021-10-15 | 詹森药业有限公司 | Therapeutic compounds for pain and synthesis thereof |
CN108349934B (en) * | 2015-09-04 | 2021-10-22 | 詹森药业有限公司 | Therapeutic compounds for pain and synthesis thereof |
US11345681B1 (en) | 2020-06-05 | 2022-05-31 | Kinnate Biopharma Inc. | Inhibitors of fibroblast growth factor receptor kinases |
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EA014738B1 (en) | 2011-02-28 |
CA2618700A1 (en) | 2007-03-01 |
ATE482959T1 (en) | 2010-10-15 |
NZ565628A (en) | 2011-03-31 |
AU2006283453A1 (en) | 2007-03-01 |
EP1917265B1 (en) | 2010-09-29 |
BRPI0614874A2 (en) | 2011-04-19 |
MX2008002467A (en) | 2008-04-07 |
NO20080594L (en) | 2008-05-16 |
EP1917265A1 (en) | 2008-05-07 |
US20070197579A1 (en) | 2007-08-23 |
EA200800656A1 (en) | 2008-08-29 |
US20100197720A1 (en) | 2010-08-05 |
US7732607B2 (en) | 2010-06-08 |
DE602006017235D1 (en) | 2010-11-11 |
CN101248073A (en) | 2008-08-20 |
KR20080035649A (en) | 2008-04-23 |
HK1115594A1 (en) | 2008-12-05 |
IL189204A0 (en) | 2009-08-03 |
ZA200801242B (en) | 2009-02-25 |
JP2009506037A (en) | 2009-02-12 |
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