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Azabicyclic-Substituted Fused-Heteroaryl

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Azabicyclic-Substituted Fused-Heteroaryl (19) & (11) EP 1 432 707 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C07D 453/02 (2006.01) C07D 487/08 (2006.01) 28.03.2012 Bulletin 2012/13 A61K 31/439 (2006.01) A61P 25/18 (2006.01) A61P 25/28 (2006.01) (21) Application number: 02778286.1 (86) International application number: (22) Date of filing: 01.10.2002 PCT/US2002/029827 (87) International publication number: WO 2003/029252 (10.04.2003 Gazette 2003/15) (54) AZABICYCLIC-SUBSTITUTED FUSED-HETEROARYL COMPOUNDS FOR THE TREATMENT OF DISEASE AZABICYCLISCH- SUBSTITUIERTE ANNELIERTE HETEROARYL-VERBINUNGEN FÜR DIE BEHANDLUNG VON KRANKHEITEN COMPOSES D’HETEORARYLE FUSIONNE SUBSTITUES PAR AZABICYCLO UTILES POUR LE TRAITEMENT DE MALADIES (84) Designated Contracting States: • WISHKA, Donn, G. AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Kalamazoo, MI 49006-1993 (US) IE IT LI LU MC NL PT SE SK TR • REITZ, Steven Charles Designated Extension States: Toledo, OH 43615 (US) AL LT LV MK RO SI • GROPPI, Vincent, E., Jr. Kalamazoo, MI 49006 (US) (30) Priority: 02.10.2001 US 326565 P 02.10.2001 US 326629 P (74) Representative: Lane, Graham Mark Hamilton 15.11.2001 US 334886 P Pfizer 12.12.2001 US 339633 P European Patent Department 23-25, avenue du Docteur Lannelongue (43) Date of publication of application: 75668 Paris Cedex 14 (FR) 30.06.2004 Bulletin 2004/27 (56) References cited: (73) Proprietor: Pharmacia & Upjohn Company LLC WO-A-00/42044 WO-A-01/36417 Kalamazoo, MI 49001 (US) WO-A-02/15662 WO-A-02/16358 WO-A-98/54181 US-A- 5 998 429 (72) Inventors: • WALKER, Daniel, Patrick • M. BENCHERIF ET. AL.: "The Heterocyclic Kalamazoo, MI 49009 (US) Substituted Pyridine Derivative 2-(3-pyridinyl)-1- • PIOTROWSKI, David, W. Azabicyclo[2.2.2]octane (RJR-2429). A Selective Portage, MI 49024 (US) Ligand at Nicotinic Acetylcholine Receptors." • JACOBSEN, Eric, Jon JOURNAL OF PHARMACEOLOGY AND Richland, MI 49083 (US) EXPERIMENTAL THERAPEUTICS, vol. 284, no. 3, • ACKER, Brad, A. 1998, pages 886-94, XP001077007 Kalamazoo, MI 49009 (US) Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 1 432 707 B1 Printed by Jouve, 75001 PARIS (FR) EP 1 432 707 B1 Description FIELD OF INVENTION 5 [0001] Nicotinic acetylcholine receptors (nAChRs) play a large role in central nervous system (CNS) activity. Partic- ularly, they are known to be involved in cognition, learning, mood, emotion, and neuroprotection. There are several types of nicotinic acetylcholine receptors, and each one appears to have a different role in regulating CNS function. Nicotine affects all such receptors, and has a variety of activities. Unfortunately, not all of the activities are desirable. In fact, o ne of the least desirable properties of nicotine is its addictive nature and the low ratio between efficacy and safety. The 10 present invention relates to molecules that have a greater effect upon theα 7 nAChRs as compared to other closely related members of this large ligand-gated receptor family. Thus, the invention provides compounds that are active drug molecules with fewer side effects. BACKGROUND OF THE INVENTION 15 [0002] Cell surface receptors are, in general, excellent and validated drug targets. nAChRs comprise a large family of ligand-gated ionchannels thatcontrol neuronal activity andbrain function.These receptors have a pentameric structure. In mammals, this gene family is composed of nine alpha and four beta subunits that assembleco- to form multiple subtypes of receptors that have a distinctive pharmacology. Acetylcholine is the endogenous regulator of all of the 20 subtypes, while nicotine non-selectively activates all nAChRs. [0003] The α7 nAChR is one receptor system that has proved to be a difficult target for testing. Native α7 nAChR is not routinely able to be stably expressed in most mammalian cell lines (Cooper and Millar, J. Neurochem., 1997, 68 (5): 2140-51). Another feature that makes functional assays ofα 7 nAChR challenging is that the receptor is rapidly (100 milliseconds) inactivated. This rapid inactivation greatly limits the functional assays that can be used to measure channel 25 activity. [0004] Recently, Eisele et al. has indicated that a chimeric receptor formed between the N-terminal ligand binding domain of the α7 nAChR (Eisele et al., Nature, 366 (6454), p 479-83, 1993), and the pore forming C- terminal domain of the 5-HT3 receptor expressed well in Xenopus oocytes while retaining nicotinic agonist sensitivity. Eisele et al. used the N-terminus of the avian (chick) form of the α7 nAChR receptor and the C-terminus of the mouse form of the 5- HT3 gene. 30 However, under physiological conditions the α7 nAChR is a calcium channel while the 5- HT3R is a sodium and potassium channel. Indeed, Eisele et al. teaches that the chickenα 7 nAChR/ mouse 5-HT3R behaves quite differently than the native α7 nAChR with the pore element not conducting calcium but actually being blocked by calcium ions. WO 00/73431 A2 reports on assay conditions under which the 5-HT3R can be made to conduct calcium. This assay may be used to screen for agonist activity at this receptor. 35 [0005] US Patent 6,054,464 discloses azabicyclic esters of carbamic acids useful in therapy, especially in the treatment or prophylaxis of psychotic disorders and intellectual impairment disorders, as well as intermediates and use of inter- mediates in synthesis. [0006] US Patent 5,977,144 discloses compositions for benzylidene- and cinnamylidene-anabaseines and methods for using these compositions for treating conditions associated with defects or malfunctioning of nicotinic subtypes brain 40 receptors. These compositions target the α7 receptor subtype with little or no activation of the α4β2 or other receptor subtypes. [0007] US Patent 5,599,937 discloses heteroaromatic quinuclidines used for treating diseases related to muscarinic receptor function. [0008] US Patent 5,561,149 discloses the use of a mono or bicyclic carbocyclic, or heterocyclic carboxylic acid, ester 45 or amide or an imidazolyl carbazol in the manufacture of a medicament suitable for the treatment of stress-related psychiatric disorders, for increasing vigilance, for the treatment of rhinitis or serotonin-induced disorders and/or coad- ministration with another active agent to increase the bioavailability thereof, or for nasal administration. [0009] US Patent 5,543,426 discloses the use of certain 3,7-disubstituted indole compounds for treating depression or cognitive disorders. 50 [0010] US Patent 5,434,161 discloses imidazopyridines as serotonergic 5-HT3 antagonists. [0011] US Patent 5,362,740 discloses dihydrobenzofuran carboxamides useful in treating CNS disorders, but motility disorders, and/or emisis and/or pain in mammals, and/or migraine. [0012] US Patent 5,352,685 discloses thieno[3,2-b]pyridine derivatives effective for the prevention and therapeutical treatment of the symptoms caused by gastric hypanakinesis, such as heartburn, abdominal distension feeling, anorexia, 55 unpleasant feeling on upper abdomen, abdominalgia, nausea, vomiting, etc. caused by the underlying diseases such as acute and chronic gastritis, stomach and duodenum ulcer, gastroneurosis, gastroptosis, etc. [0013] US Patent 5,342,845 discloses indole derivatives and drugs. The compound of the invention is disclosed as being effective as a gastrointestinal motor activity regulator, antimigraine, antipsychotic or antianxiety drug and for 2 EP 1 432 707 B1 dementia or orthostatic hypotension. [0014] US Patent 5,322,951 discloses certain 1-(2,3- dihydro-indole)carbonyl intermediates useful for preparing 1-(2,3- dihydro)-1-carboxamide final products that possess 5-HT M-receptor antagonist activity. [0015] US Patent 5,272,154 discloses 3,7 substituted indole and indazole compounds and pharmaceutical composi- 5 tions containing them and are disclosed as being useful for the treatment of psychiatric disorders. [0016] US Patent 5,217,975 discloses azabicyclic compounds for treating dementia. [0017] US Patent 5,039,680 discloses 5-HT3 antagonists in preventing or reducing dependency on dependency- inducing agents. [0018] US Patent 5,001,133 discloses substituted benzoic acid heterocyclic amides and esters as being serotonin M 10 antagonists. [0019] US Patent 4,985,437 discloses the use of certain compounds which act as antagonists of 5-hydroxytryptamine (5-HT) at 5-HT3 receptors for the treatment of cognitive disorders such as attentional and memory deficits and dementia states. [0020] US Patent 4,983,600 discloses heterocyclic compounds useful as 5-HT3 antagonists. 15 [0021] US Patent 4,973,594 discloses the use of compounds which act as antagonists of 5- hydroxytryptamine (5-HT) at 5-HT3 receptors for the treatment of depression. [0022] US Patent 4,937,247 discloses 1-acyl indazoles that are disclosed as having 5-HT3 antagonist activity. [0023] US Patent 4,935,511 discloses benzoxazine and benzoxazepin carboxamide 5-HT3 antagonists properties including CNS, anti-emetic and gastric prokinetic activity and which are void of any significant D 2 receptor binding affinity. 20 [0024] US Patent 4,921,982 discloses 5-halo-2,3- dihydro-2,2-dimethylbenzofuran-7-carboxylic acids which are useful as intermediates for 5-HT3 antagonists. [0025] US Patent 4,920,219 discloses substituted saturated and unsaturated indole quinoline and benzazepine car- boxamides and their valuable use as 5- HT3 antagonists having CNS and gastric prokinetic activity void of any significant D2 receptor binding properties. 25 [0026] US Patent 4,920,127 discloses substituted indoles and their use as 5-H3 receptor antagonists.
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