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WO1997011072A1 - Nouveaux composes azacycliques ou azabicycliques a substitution - Google Patents

Nouveaux composes azacycliques ou azabicycliques a substitution Download PDF

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Publication number
WO1997011072A1
WO1997011072A1 PCT/DK1996/000401 DK9600401W WO9711072A1 WO 1997011072 A1 WO1997011072 A1 WO 1997011072A1 DK 9600401 W DK9600401 W DK 9600401W WO 9711072 A1 WO9711072 A1 WO 9711072A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
azabicyclo
anyone
compound according
pyridylmethylene
Prior art date
Application number
PCT/DK1996/000401
Other languages
English (en)
Inventor
Preben Houlberg Olesen
John Bondo Hansen
Holger C. Hansen
Original Assignee
Novo Nordisk A/S
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Novo Nordisk A/S filed Critical Novo Nordisk A/S
Priority to AU70835/96A priority Critical patent/AU7083596A/en
Priority to EP96931759A priority patent/EP0853621A1/fr
Priority to JP9512337A priority patent/JPH11512443A/ja
Publication of WO1997011072A1 publication Critical patent/WO1997011072A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems

Definitions

  • the present invention relates to heterocyclic compounds which are cholinergic ligands selective for neuronal nicotinic channel receptors, to methods for their preparation, to pharmaceutical compositions comprising them, and to their use in treating cognitive, neurological and mental disorders, such as dementia and anxiety, which are characterized by decreased cholinergic function.
  • the invention also relates to a method of treating Parkinson's disease by modulating the process of dopamine secretion, a method of treating or preventing withdrawal symptoms caused by cessation of chronic or long term use of tobacco products, as well as a method for treating obesity.
  • Nicotinic and muscarinic receptors are the two distinct types of choliner ⁇ gic receptors named after their selectivity for muscarine and nicotine, respectively.
  • the cholinergic system is the neurotransmitter system that best correlates with memory and cognitive functions.
  • SDAT a cholinergic hypothesis for senile dementia of the Alzheimer type
  • mAChR muscarinic acetylcholine receptors
  • nAChR nicotinic acetylcholine receptors
  • Parkinson's disease is a debilitating neurodegenerative disease, presently of unknown etiology, characterized by tremors and muscular rigidity.
  • nicotine may also have beneficial effects in PD.
  • Nicotine has also shown beneficial effects in Tourette's syndrome (Sanberg et al., Biomed. Phamacother., Vol. 43, pp. 1 9-23, (1 989)). Alleviation of negative psychotic symptoms, known as the hypofrontality syndrome in schizophrenia, by nicotinic agonists, have been suggested by data showing that nicotine stimulates dopamine release in the nucleus accumbens more potently than in stria ⁇ tum, (Rowell et al. J. Neurochem., Vol. 49, pp. 1449-1454, (1 987); Giorguieff-Chesselet et al., Life Sciences, Vol. 25, pp. 1257-1 262,
  • the present invention relates to novel substituted azacyclic or azabicyclic compounds of formula la, lb and Ic selected from the following:
  • x is 1 ,2,3,4 or 5; and n is 1 , 2 or 3; and m is 1 , 2 or 3; and p is 0, 1 or 2; and s is 0, 1 or 2; and t is 0, 1 or 2; and u is 0, 1 or 2; and
  • R is hydrogen or C ⁇ -alkyl; and G is selected among the following hetero- cycles
  • R 1 , R 2 , R 3 and R 4 independently are hydrogen, halogen, -NO 2 , -CN, -OR 5 , -SR 5 , C L ⁇ -alkylC L ⁇ -polyfluoroalkyl, C 2 . 6 -alkenyl,
  • Examples of pharmaceutically acceptable salts include inorganic and organic acid addition salts such as hydrochloride, hydrobromide, sul ⁇ phate, phosphate, acetate, fumarate, maleate, citrate, lactate, tartrate, oxalate, or similar pharmaceutically-acceptable inorganic or organic acid addition salts, and include the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science, 6_6, 2 ( 1 977) which are hereby incorporated by reference.
  • the compounds of formula I may exist as geometric and optical isomers and all isomers and mixtures thereof are included herein. Isomers may be separated by means of standard methods such as chromatographic techniques or fractional crystallization of suitable salts.
  • C 3 . 6 -cycloalkyl refers to a radical of a saturated cyclic hydrocarbon having from 3 to 6 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl and the like.
  • C 2 . 6 -alkenyl refers to an unsaturated hydrocar ⁇ bon chain having from 2 to 6 carbon atoms and at least one double bond such as vinyl, 1 -propenyl, allyl, isopropenyl, n-butenyl, n-pentenyl and n- hexenyl and the like.
  • Polyfluoro in "C L ⁇ -polyfluoroalkyl” means a C ⁇ -alkyl substituted with from 2 to 13 fluorine atoms such as -CF 3 , -CH 2 -CF 3 , -CH 2 -CH 2 -CF 3 and - CH 2 -CH 2 -CH 2 -CF 3 and the like.
  • C 2 . 6 -alkynyl refers to an unsaturated hydrocar ⁇ bon chain having from 2 to 6 carbon atoms and at least one triple bond such as -C ⁇ CH, -CH 2 -CH 2 -C ⁇ CH, -CH(CH 3 )-C ⁇ CH, -C ⁇ CCH 3 , -CH 2 C ⁇ CH, -CH(CH 3 )C ⁇ H and the like.
  • C 2 . 6 -alkoxyalkyl as used herein means a group of 2 to 6 carbons inter ⁇ rupted by an O such as -CH 2 -0-CH 3 , -CH 2 -CH 2 -0-CH 3 , -CH 2 -0-CH 2 -CH 3 and the like.
  • C 2 . 6 -alkylthioalkyl means a group of 2 to 6 carbons interrupted by an S such as -CH 2 -S-CH 3 , -CH 2 -CH 2 -S-CH 3 , -CH 2 -S-CH 2 -CH 3 and the like.
  • C 2 . 6 -alkylaminoalkyl means a group of 2 to 6 carbons interrupted by an N such as -CH 2 -NH-CH 3 , -CH 2 -CH 2 -NH-CH 3 , -CH 2 -NH-CH 2 -CH 3 and the like.
  • halogen means fluorine, chlorine, bromine and iodine.
  • R represents H or C ⁇ -alkyl.
  • a preferred value is 2, 3 or 4
  • n, m and p is preferably respectively 2, 1 and 0 or 2, 2 and 0 or 3, 1 and 0 and s
  • t and u is preferably re- spectively 1 , 1 and 0 or 1 , 2 and 0 or 1 , 2 and 1 .
  • Preferred compounds include:
  • the invention also relates to a method of preparing the above mentioned compounds of formula I. These methods comprise: a) reacting a compound of formula II, III or IV
  • R 5 , R 6 , R 7 , R 8 and R 9 independently are straight or branched C ⁇ -alkyl, to give com ⁇ pounds of the general formula la, lb or Ic;
  • R 10 , R 11 and R 12 independently are straight or branched C ⁇ -alky! and -A-B-C-D-E- have the meanings defined above, to give compounds of the general formula la, lb or Ic.
  • the pharmacological properties of the compounds of the invention can be illustrated by determining their capability to inhibit the specific binding of 3 H-methylcarbamylcholine ( 3 H-MCC) (Abood and Grassi, Biochem. Phar ⁇ macol., Vol. 35, pp. 41 99-4202, (1 986)).
  • 3 H-MCC 3 H-methylcarbamylcholine
  • 3 H-MCC labels the nicotinic receptors in the CNS.
  • the inhibitory effect on 3 H-MCC binding reflects the affinity for nicotinic acetylcholine receptors.
  • Fresh or frozen rat, brain tissue (hippocampus or cortex) was homoge- - io ⁇
  • assay buffer 50mM Tris-HCI, pH 7.4, 1 20 mM NaCI, 5 mM KCI, 2 mM CaCI 2 , 1 mM MgCI 2
  • Pellets were subsequently reconstituted in assay buffer and an appropri ⁇ ate amount of tissue sample was mixed in tubes with 3 H-methylcarba- mylcholine (NEN, NET-951 ; final concentration 2 nM) and test drug.
  • the tubes were incubated at 0 °C for 60 min. Unbound ligand was separated from bound ligand by vacuum filtration through GF/B filters presoaked in 0.5 % polyethylenimine.
  • IC 50 values of the test compounds were determined by nonlinear regression analyses (GraphPad InPlot).
  • the pharmacological properties of the compounds of the invention can also be illustrated by determining their capability to inhibit the specific binding of 3 H-Oxotremorine-M ( 3 H-Oxo). Birdsdall N.J.M., Hulme E.C., and Burgen A.S.V. (1 980). "The Character of Muscarinic Receptors in Different Regions of the Rat Brain” . Proc. Roy. Soc. London (Series B) 207, 1 .
  • 3 H-Oxo labels muscarinic receptor in the CNS (with a preference for agonist domains of the receptors).
  • Three different sites are labelled by 3 H- Oxo. These sites have affinity of 1 .8, 20 and 3000 nM, respectively. Using the present experimental conditions only the high and medium affinity sites are determined.
  • the inhibitory effects of compounds on 3 H-Oxo binding reflects the affinity for muscarinic acetylcholine receptors.
  • Fresh cortex (0.1 - 1 g) from male Wistar rats (1 50-250 g) is homogenized for 5- 10 s in 1 0 ml 20 mM Hepes pH: 7.4, with an Ultra-Turrax homogenizer. The homogenizer is rinsed with 10 ml of buffer and the combined sus ⁇ pension centrifuged for 1 5 min. at 40,000 x g. The pellet is washed three times with buffer. In each step the pellet is homogenized as before in 2 x 1 0 ml of buffer and centrifuged for 10 min. at 40,000 x g.
  • the final pellet is homogenized in 20 mM Hepes pH: 7.4 ( 1 00 ml per g of original tissue) and used for binding assay. Aliquots of 0.5 ml is added 25 ul of test solution and 25 ul of 3 H-Oxotremorine (1 .0 nM, final concentra- tion) mixed and incubated for 30 min. at 25°C. Non-specific binding is determined in triplicate using arecoline ( 1 ug/ml, final concentration) as the test substance. After incubation samples are added 5 ml of ice-cold buffer and poured directly onto Whatman GF/C glass fiber filters under suction and immediately washed 2 times with 5 ml of ice-cold buffer. The amount of radioactivity on the filters are determined by conventional liquid scintillation counting. Specific binding is total binding minus non specific binding.
  • Test substances are dissolved in 1 0 ml water (if necessary heated on a steam-bath for less than 5 min.) at a concentration of 2.2 mg/ml. 25-
  • IC 50 the concentration (nM) of the test substance which inhibits the specific binding of 3 H-Oxo by 50%).
  • IC 50 (applied test substance concentration) x(C x /C 0 -C x )nM
  • Table I illustrates the affinity of the compounds of the present invention for nicotinic and muscarinic receptors as determined by 3 H-MCC and 3 H- Oxo binding to rat cortical receptors.
  • the compounds show selective affinity for nicotinic receptors as compared to muscarinic receptors, i.e OXO/MCC > 1 .
  • the compounds of the invention are effective over a wide dosage range.
  • dosages from about 0.05 to about 1 00 mg, preferably from about 0.1 to about 100 mg, per day may be used.
  • a most preferable dosage is about 10 mg to about 70 mg per day.
  • the exact dosage will depend upon the mode of administration, form in which administered, the subject to be treated and the body weight of the subject to be treated, and the preference and experience of the physician or veterinarian in charge.
  • the route of administration may be any route, which effectively trans ⁇ ports the active compound to the appropriate or desired site of action, such as oral or parenteral e.g. rectal, transdermal, subcutaneous, intra ⁇ venous, intraurethral, intramuscular, topical, intranasal, ophthalmic solution or an ointment, the oral route being preferred.
  • Typical compositions include a compound of formula la, lb or Ic or a phar ⁇ maceutically acceptable acid addition salt thereof, associated with a phar ⁇ maceutically acceptable carrier.
  • conventional techniques for the preparation of pharmaceutical compositions may be used.
  • the active compound will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a ampoule, capsule, sachet, paper, or other container.
  • a carrier which may be in the form of a ampoule, capsule, sachet, paper, or other container.
  • the carrier serves as a diluent, it may be solid, semisolid, or liquid material which acts as a vehicle, excipient, or medium for the active compound.
  • the active compound can be adsorbed on a granular solid container for example in a sachet.
  • suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxyl- ated castor oil, gelatine, lactose, amylose, magnesium stearate, talc, silicic acid, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, hydroxymethylcellulose and polyvinylpyrrolidone.
  • the pharmaceutical preparations can be sterilized and mixed, if desired, with auxiliary agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or colouring substances and the like, which do not deleteri- ously react with the active compounds.
  • injectable solutions or suspensions preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.
  • Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application.
  • Preferable carriers for tablets, dragees, or capsules include lactose, corn starch, and/or potato starch.
  • a syrup or elixir can be used in cases where a sweetened vehicle can be employed.
  • the compounds are dispensed in unit form comprising from about 1 to about 1 00 mg in a pharmaceutically acceptable carrier per unit dosage.
  • a typical tablet appropriate for use in this method, may be prepared by conventional tabletting techniques and contains:
  • reaction mixture was stirred for 45 min., then cooled to -60 °C , and 1 - azabicyclo[2.2.1 ]heptan-3-one ( 0.85 g, 7.6 mmol dissolved in tetrahy- drofuran ( 1 0 ml) was added.
  • the reaction mixture was stirred at -60 °C for 1 .5 hours, then quenched with water (100 ml), and made alkaline with solid potassium carbonate. The water phase was extracted with ether (3x75 ml). The combined organic extracts were dried over magne ⁇ sium sulfate and evaporated.
  • reaction mixture was stirred for 45 min., then cooled to -60 °C , and 1 -benzyl-3-piperidone (2.3 g, 10.0 mmol ) dissolved in tetrahy- drofurane ( 1 0 ml) was added.
  • the reaction mixture was stirred at -60 °C for 1 .5 hours, then quenched with water (100 ml). The water phase was extracted with ether (3x75 ml). The combined organic extracts were dried over magnesiumsulfate and evaporated. The residue was purified by column chromatography on silica (eluent: ethylacetate).
  • the first frac ⁇ tions contained the (Z)-benzyl-3-(3-pyridylmethylene)piperidine isomer, which was isolated in 25 % (650 mg) yield.
  • the next fractions contained the (E)-benzyl-3-(3-pyridylmethylene)piperidine isomer, which was iso ⁇ lated in 23 % (600 mg ) yield.

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

Abstract

Cette invention a trait à des composés hétérocycliques à activité thérapeutique, à des procédés permettant leur préparation ainsi qu'à des compositions pharmaceutiques les contenant. Ces nouveaux composés se révèlent utiles dans le traitement de maladies du système nerveux central liées à un dysfonctionnement du système cholinergique nicotinique.
PCT/DK1996/000401 1995-09-22 1996-09-20 Nouveaux composes azacycliques ou azabicycliques a substitution WO1997011072A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
AU70835/96A AU7083596A (en) 1995-09-22 1996-09-20 Novel substituted azacyclic or azabicyclic compounds
EP96931759A EP0853621A1 (fr) 1995-09-22 1996-09-20 Nouveaux composes azacycliques ou azabicycliques a substitution
JP9512337A JPH11512443A (ja) 1995-09-22 1996-09-20 新規な置換アザ環式またはアザ二環式化合物

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
DK106395 1995-09-22
DK1063/95 1995-09-22
DK1166/95 1995-10-16
DK116695 1995-10-16

Publications (1)

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WO1997011072A1 true WO1997011072A1 (fr) 1997-03-27

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PCT/DK1996/000401 WO1997011072A1 (fr) 1995-09-22 1996-09-20 Nouveaux composes azacycliques ou azabicycliques a substitution

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EP (1) EP0853621A1 (fr)
JP (1) JPH11512443A (fr)
AU (1) AU7083596A (fr)
WO (1) WO1997011072A1 (fr)

Cited By (32)

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WO1998054181A1 (fr) * 1997-05-30 1998-12-03 Neurosearch A/S Derives de 8-azabicyclo[3.2.1]oct-2-ene et -octane utilises comme ligands cholinergiques de recepteurs nicotiniques de l'ach
WO1998054182A1 (fr) * 1997-05-30 1998-12-03 Neurosearch A/S Derives de 9-azabicyclo(3.3.1)non-2-ene et nonane utilises comme ligands cholinergiques de recepteurs nicotiniques de l'ach.
WO1999032117A1 (fr) * 1997-12-22 1999-07-01 Sibia Neurosciences, Inc. Nouveaux composes pyridine substitues utiles en tant que modulateurs des recepteurs de l'acetylcholine
WO1999051602A1 (fr) * 1998-04-02 1999-10-14 R.J. Reynolds Tobacco Company Derives de l'azatricyclo[3.3.1,1] decane et preparations pharmaceutiques les contenant
WO2000034276A1 (fr) * 1998-12-11 2000-06-15 R.J. Reynolds Tobacco Company Derives a tete de pont pyridyle et leurs analogues, compositions pharmaceutiques et leur utilisation comme inhibiteurs des recepteurs cholinergiques nicotiniques
US6362009B1 (en) 1997-11-21 2002-03-26 Merck & Co., Inc. Solid phase synthesis of heterocycles
US6420395B1 (en) 1997-05-30 2002-07-16 Neurosearch A/S Azacyclooctane and heptane derivatives, their preparation and use in therapy
US6538003B1 (en) * 1999-03-05 2003-03-25 Sanofi-Synthelabo Pyridopyranoazepine derivatives, their preparation and their therapeutic application
US6579878B1 (en) 2000-07-07 2003-06-17 Targacept, Inc. Pharmaceutical compositions and methods for use
US6624167B1 (en) 2000-08-04 2003-09-23 Targacept, Inc. Pharmaceutical compositions and methods for use
US6630467B2 (en) * 1996-10-30 2003-10-07 Pfizer Inc. Pyridone-fused azabicyclic- or cytisine derivatives, their preparation and their use in addiction therapy
US6642246B1 (en) * 1999-10-18 2003-11-04 Astrazeneca Ab Quinuclidine acrylamides
US6852721B2 (en) 2000-05-25 2005-02-08 Targacept, Inc. Pharmaceutical compositions and methods for use
US6953855B2 (en) 1998-12-11 2005-10-11 Targacept, Inc. 3-substituted-2(arylalkyl)-1-azabicycloalkanes and methods of use thereof
US7101896B2 (en) 1999-11-01 2006-09-05 Targacept, Inc. Pharmaceutical compositions and methods for use
EP1977746A1 (fr) 2007-04-02 2008-10-08 The Parkinson's Institute Procédés et compositions pour la réduction des effets indésirables de traitements thérapeutiques
US7579362B2 (en) 2002-09-04 2009-08-25 Novartis Ag Aza-bicycloalkyl ethers and their use as alpha7-nAChR agonists
CZ301925B6 (cs) * 1997-12-31 2010-08-04 Pfizer Products Inc. Azapolycyklické deriváty s anelovanou arylskupinou, jejich použití, farmaceutické kompozice na jejich bázi a meziprodukty pro jejich výrobu
US7981906B2 (en) 2007-08-02 2011-07-19 Targacept, Inc. (2S,3R)-N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl-benzofuran-2-carboxamide, novel salt forms, and methods of use thereof
US8048885B2 (en) 2005-12-16 2011-11-01 Novartis Ag Organic compounds
US8173667B2 (en) 2005-10-21 2012-05-08 Novartis Ag 1-aza-bicycloalkyl derivatives
US8609662B2 (en) 2004-07-14 2013-12-17 Novartis Ag 3-(heteroaryl-oxy)-2-alkyl-1-aza-bicycloalkyl derivatives as alpha. 7-nachr ligands for the treatment of CNS diseases
US8759552B2 (en) 2009-07-31 2014-06-24 South Bank University Enterprises Ltd. Liquid phase epoxidation process
US8759346B2 (en) 2005-12-16 2014-06-24 Novartis Ag Organic compounds
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
US8933090B2 (en) 2004-06-18 2015-01-13 Novartis Ag 1-aza-bicyclo[3.3.1]nonanes
US9724340B2 (en) 2015-07-31 2017-08-08 Attenua, Inc. Antitussive compositions and methods
US11285306B2 (en) 2017-01-06 2022-03-29 Morningside Venture Investments Limited Transdermal drug delivery devices and methods
US11400266B2 (en) 2015-01-28 2022-08-02 Morningside Venture Investments Limited Drug delivery methods and systems
US11471424B2 (en) 2004-09-13 2022-10-18 Morningside Venture Investments Limited Biosynchronous transdermal drug delivery
US11596779B2 (en) 2018-05-29 2023-03-07 Morningside Venture Investments Limited Drug delivery methods and systems
US12397141B2 (en) 2018-11-16 2025-08-26 Morningside Venture Investments Limited Thermally regulated transdermal drug delivery system

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EP0414394A2 (fr) * 1989-08-05 1991-02-27 Beecham Group Plc Dérivés azabicycliques ayant une affinité pour le récepteur muscarinique
EP0638569A1 (fr) * 1993-02-17 1995-02-15 Kanegafuchi Kagaku Kogyo Kabushiki Kaisha Compose azote bicyclique

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AU7083596A (en) 1997-04-09
EP0853621A1 (fr) 1998-07-22
JPH11512443A (ja) 1999-10-26

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