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WO1994018201A1 - Derive d'isoxazoleoxy - Google Patents

Derive d'isoxazoleoxy Download PDF

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Publication number
WO1994018201A1
WO1994018201A1 PCT/JP1994/000201 JP9400201W WO9418201A1 WO 1994018201 A1 WO1994018201 A1 WO 1994018201A1 JP 9400201 W JP9400201 W JP 9400201W WO 9418201 A1 WO9418201 A1 WO 9418201A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
azabicyclo
heptanoxy
acceptable salts
atom
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/JP1994/000201
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English (en)
Japanese (ja)
Inventor
Susumu Sato
Junichi Sakai
Nobuyuki Ohkawa
Masao Kozuka
Nobuyoshi Iwata
Mitsuo Nagano
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sankyo Co Ltd
Original Assignee
Sankyo Co Ltd
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 Sankyo Co Ltd filed Critical Sankyo Co Ltd
Priority to AU60105/94A priority Critical patent/AU6010594A/en
Publication of WO1994018201A1 publication Critical patent/WO1994018201A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • 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

Definitions

  • the present invention relates to an isoxazoleoxy derivative (I) having an anti-dementia, cerebral function improving action, and the like.
  • the heart and intestinal tract have many M2 receptors, while the cerebral cortex and the hippocampus, which are responsible for memory and cognitive functions, have many Ml receptors, so M1 agonists separated from M2 as much as possible If found, an anti-dementia drug with fewer side effects can be developed.
  • Ml receptors excite neurons in the postsynaptic membrane, whereas M2 receptors in presynaptic terminals suppress the release of acetylcholine. Therefore, a compound having high selectivity for M1 can excite the postsynaptic membrane more, so that the drug effect is expected to be stronger.
  • the present invention has found a compound that binds to the MI receptor more selectively than any of the previously known compounds, and has completed the present invention.
  • the present invention uses the formula
  • R 1 represents a hydrogen atom, a halogen atom, a lower alkyl group or a cycloalkyl group
  • halogen atom in the definition of R ′, R 4 to R 7 and the substituent group A represents a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, and is preferably a fluorine atom, a chlorine atom, or a bromine atom. And more preferably a chlorine atom.
  • lower alkyl group in the definition of R 1 , R 2 , R 4 to R 7 and the substituent group A means, for example, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, S-butyl, t-butyl -Butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethyl butyl, 2, 2-dimethyl Chirubuchiru, 1, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2, 3-C, such as dimethylbutyl and 2-Echirubuchiru, - C 6 linear Or branched chain al Represents a kill group, preferably a C
  • the ⁇ cycloalkyl group '' in the definition of R 1 and R 2 may be a fused ring such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, or adamantyl.
  • It represents a saturated cyclic hydrocarbon group, preferably represents a C 3 -c 6 saturated cyclic hydrocarbon group, and more preferably represents cyclopropyl.
  • aromatic heterocyclic group of the "aromatic heterocyclic group having or not having a substituent selected from the following substituent group A" in the definition of R 2 means a sulfur atom, an oxygen atom or a nitrogen atom.
  • lower alkoxy group in the definition of R 4 to R 7 and the substituent group A indicates a group bonded to the above “lower alkyl group” force ⁇ oxygen atom, for example, methoxy, ethoxy, propoxy, Isopropoxy, n-butoxy, isobutoxy, S-butoxy, t-butoxy, n-pentoxy, isopentoxy, 2-methylbutoxy, neopentoxy, n-hexyloxy, 4-methylpentoxy, 3-methylpentoxy, 2- Methylpentoxy, 3,3-dimethylbutoxy, 2,2-dimethylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,3-dimethylbutoxy C, such as carboxymethyl - C 6 represents a linear or branched alkoxy group, preferably a c, - a c 4 linear or branched alkoxy group, is more preferably
  • the “halomethyl group” in the definition of R 4 to R 7 represents a group in which one to three groups selected from the above “halogen atom” are bonded to a methyl group, for example, fluoromethyl, chloromethyl, bromomethyl A methyl, difluoromethyl, dichloromethyl, dibromomethyl, iodomethyl, trifluoromethyl, trichloromethyl, tripromomethyl or triodomethyl group, preferably methylol substituted with 1 to 3 fluorine atoms or chlorine atoms And more preferably trifluoromethyl or trichloromethyl.
  • the ⁇ lower alkylamino group '' in the definition of R 4 to R 7 and the substituent group A is the above-mentioned ⁇ lower alkyl group '' which is a group bonded to one or two amino groups, for example, methylamino, ethylamino, Propylamino, isopropylamino, butylamino, isobutylamino, s-butylamino, t-butylamino, n-pentylamino, isopentylamino, 2-methylbutylamino, neopentylamino, 1-ethylpropylamino, n —Hexylamino, 4-methylpentylamino, 3-methylpentylamino, 2-methylpentylamino, 1-methylpentylamino, 3,3-dimethylbutylamino, 2,2-dimethylbutylamino, 1,1 -Dimethylbutylamin
  • lower alk noisy Rua amino group in the definition of R 4 to R 7 in the above, for example Horumiruamino, Asechiruamino, propionyl Rua Mino, Buchiriruamino, I Su Wu dust Rua Mino, Bareriruamino, isovaleryl Rua Mino, Bibaroiruamino to, the Kisanoiruamino
  • a C, — C 6 straight-chain or branched-chain alkanoyl group is bonded to an amino group, preferably a C, -C 4 straight-chain or branched alkanoylamino group; Preferably, it is formylamino, acetylamino or propionylamino.
  • preferred compounds include
  • R 1 is a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a d-C 4 linear or branched alkyl group or a C 3 -C 6 saturated cyclic hydrocarbon group,
  • R 2 is a hydrogen atom, C, one C 4 straight or branched chain alkyl group, C 3 -Ce saturated cyclic hydrocarbon group or a methyl, Echiru, hydroxyl, main butoxy, Etokin, fluorine atom, chlorine atom, nitro group Or a phenyl group which may have the same or different amino group as a substituent,
  • R 1 force ⁇ hydrogen atom, fluorine atom, chlorine atom, methyl, ethyl, propyl, isopropyl, cyclopropyl or cyclohexyl,
  • R 2 may have a hydrogen atom, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopentyl, cyclohexyl or methyl, ethyl, methoxy, fluorine or chlorine atom as the same or different substituents
  • Compounds that are phenyl groups can be mentioned.
  • R 1 is hydrogen atom, chlorine atom, methyl or ethyl, W
  • R 2 is a hydrogen atom, methyl, ethyl, cyclopropyl or phenyl group.
  • Suitable compounds represented by the general formula (I) obtained by the present invention include, for example, the following compounds.
  • Pent Indicates penchinore.
  • the preferred compound numbers are 1, 2, 3, 4, 5, 10, 10, 11, 12, 13, 13, 14, 15, 16, 20, 20, 21, 2, 23, 24, 29, 30, 31, 31, 32, 33, 34, 35, 36, 42, 43, 44, 45, 46, 47, 48, 49, 54, 55, 56, 57, 58, 59, 60, 64, 65, 66, 67, 68, 69, 70, 71, 72, 107 , 1 108, 1 1 0, 1 1 1, 1 1 2, 1 1 3, 1 1 4, 1 2 1, 1 22, 1 2 3, 1 24, 1 2 5, 1 2 6, 1 3 0 , 13 1, 13 2, 13 3, 13 4, 13 7, 13 8, 140, 14 1, 142, 143 and 144.
  • the acid addition salt of the isoxazoleoxy derivative having the general formula (I) is preferably a halogen such as hydrofluoride, hydrochloride, hydrobromide or hydroiodide.
  • Inorganic acid salts such as danihydrogen, nitrate, perchlorate, sulfate and phosphate; lower alkane sulfonates such as methanesulfonate, trifluoromethanesulfonate and ethanesulfonate, and benzene Sulfates, aryl sulfonates such as p-toluenesulfonate, fumarate, succinate, citrate, tartrate, oxalate, maleate and other organic acid salts and glutamates, Amino acid salts such as aspartate can be mentioned.
  • the formula (I) represents one of the optical isomers or a mixture thereof.
  • the compound having the general formula (I) in the present invention can be produced by the method described below.
  • Method 1 relates to a method for producing a compound having the general formula (IV).
  • the compound (IV) of the present invention is represented by 3-hydroxyisoxazoles represented by the general formula (II) and Journal of Organic Chemistry (J. Org. Chem.) _3_4_, 3671 (1969).
  • 1-azabicyclo [2,2,1] heptane-1-ol ( ⁇ ) obtained by the method described in Bulletin Chem. Soc. Jap. 40, 2380 (1967) can be produced by a dehydration condensation reaction in an inert solvent (for example, ethers such as getyl ether and tetrahydrofuran). The reaction is carried out at a temperature of -30 ° C to 100 ° C, preferably -10 ° C to 50 ° C.
  • the reaction time varies depending mainly on the reaction temperature, the starting compound, the reaction reagent or the type of the solvent used, but is usually from 1 hour to 20 hours.
  • the compound of the present invention is collected from the reaction mixture according to a conventional method. For example, it can be obtained by adding an organic solvent immiscible with water to the reaction mixture, washing with water, and distilling off the solvent. If necessary, the obtained target compound (IV) is subjected to a conventional method, for example, recrystallization, recrystallization, C can be further purified by precipitation or chromatography Chancellor
  • R 1 and R 2 have the same meanings as described above, and M represents an alkali metal such as sodium or potassium.
  • Method 2 is an alternative to the preparation of compounds having the general formula (IV).
  • the compound (IV) of the present invention can be obtained from 3-chloroisoxazoles (V) obtained by the method described in Hemover's Berichte (Chem Ber.) 100, 330-336 (1967). 1 mol of 1 mol of 1-azabicyclo [2,2,1] heptane-13 alcohols (VI) and 1 mol of non-aqueous solvent (eg, dimethylformamide, hexamethylsulfo It can be produced by performing the reaction in an amide (such as HMPA) usually at 0 ° C to 50 ° C. The reaction time is mainly determined by the reaction temperature, the amount of the starting compound, the reaction reagent or the solvent used.
  • amide such as HMPA
  • the present invention compounds according to a conventional method, is collected from the reaction mixture.
  • the organic solvent to the reaction mixture immiscible with water is added, washed with water Can be obtained by distilling off the solvent.
  • a conventional method for example, recrystallization, can be further purified Te cowpea to reprecipitation or chromatography first prize.
  • HX is an inorganic acid such as hydrofluoric acid, hydrochloride, hydrobromic acid, hydrohalic acid such as hydroiodic acid, nitric acid, perchloric acid, sulfuric acid, phosphoric acid, etc.
  • Methanesulfonic acid Lower sulfonic acids such as trifluoromethanesulfonic acid and ethanesulfonic acid, benzenesulfonic acid, arylsulfonic acid such as P-.toluenesulfonic acid, fumaric acid, succinic acid, citric acid, tartaric acid, oxalic acid, It indicates organic acids such as maleic acid and amino acids such as glutamic acid and aspartic acid.
  • sulfonic acids such as trifluoromethanesulfonic acid and ethanesulfonic acid, benzenesulfonic acid, arylsulfonic acid such as P-.toluenesulfonic acid, fumaric acid, succinic acid, citric acid, tartaric acid, oxalic acid, It indicates organic acids such as maleic acid and amino acids such as glutamic acid and aspartic acid.
  • the above steps relate to a process for preparing a compound having the general formula (I).
  • Inorganic acids such as salts, hydrohalic acids such as hydrobromic acid and hydroiodic acid, nitric acid, perchloric acid, sulfuric acid, and dry acid; methanesulfonic acid, trifluoromethanesulfonic acid, and ethanesulfonic acid
  • Organic acids such as arylsulfonic acid such as lower alkanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid, fumaric acid, succinic acid, citric acid, tartaric acid, oxalic acid and maleic acid
  • Fine glutamic acid, amino acids such as Asuparagin acid was added, the precipitated solid was collected by filtration, it is possible to give the object of compound (I) is by recrystallization in alcohol one Honoré such as Etanoru.
  • R 2 When the substituent of the substituted phenyl group of R 2 is 0H, H 2 , alkylamino, and R 4 to R 7 are amino or alkylamino, for example, in the case of 0H, a methoxymethyl group, an acetyl group, or the like is used as a protecting group. In the case of a secondary or primary substituted amino group, a t-butoxycarbonyl group, an acetyl group, or the like is used as a protecting group, and the corresponding product is removed with an acid or an alcohol to remove the protecting group to obtain the desired product.
  • the compound having the general formula (I) of the present invention is one of the receptors for the neurotransmitter acetylcholine, which is widely distributed in the brain, according to the following Test Examples (1) and (2). It has been shown that it binds very specifically and strongly to the phosphorous receptor, and in particular to the Muscular Phosphorus 1 (Ml) receptor localized in the postsynaptic membrane. This feature is based on the fact that these compounds have few side effects on the heart or intestinal tract, etc., and are considered to be caused by damage to the acetylcholine synthesis system, such as Alzheimer's type 1 dementia, senile dementia, Huntington's disease, etc.
  • Ml Muscular Phosphorus 1
  • Examples of the form include an oral administration method using tablets, capsules, granules, powders, syrups and the like, and a parenteral administration method using injections, suppositories and the like.
  • These various preparations are prepared according to the usual methods, depending on the purpose, by adding known excipients, such as excipients, binders, disintegrants, lubricants, and flavoring agents, which are commonly used in the pharmaceutical preparation technical field. It can be used for formulation.
  • the amount used varies depending on the symptoms, age, body weight, etc., but in the case of oral administration, usually 5 to 50 mg can be administered to an adult once to three times a day.
  • test examples, preparation examples and production examples will be described more specifically.
  • a test compound and 3 H-oxotremorine-M (Oxo-M, final concentration; 3 nM) were added to a rat cerebral cortical membrane preparation, and reacted at 30 ° C. for 60 minutes. After the reaction was stopped, the 3 H radioactivity bound to the membrane sample on the filter paper was measured with a liquid scintillation counter throughout the evening.
  • a compound capable of binding to a muscarinic receptor replaces 3 H—Oxo-M and binds to a muscarinic receptor, so that the 3 H radioactivity of the membrane preparation decreases.
  • the concentration (IC50) of the compound that reduced 3 H radioactivity of the control by 50% was used as an index of the ability of the compound to bind to muscarinic receptor.
  • a test compound and 3 H-pirenzepine (Pirenzp., Final concentration: 1 nM), which selectively binds to the Ml receptor, were added to a rat cerebral cortical membrane sample in which many Ml receptors were localized, and the mixture was added to the mixture at 30 ° C The reaction was carried out for 60 minutes. Further, M 2 receptors in membranes preparations of many localized to that rat hearts binds approximately equal to M l and M 2 receptor 3 H- quinacridine base Nzoeto: a (QNB, final concentration 0. 1 2 nM) In addition, the reaction was performed at 30 degrees Celsius for 120 minutes.
  • [2,2,1] Heptaneoxy) 1-4-Chloroisoxazonole hydrochloride has a larger Magonist index than AF-102B, which is under development for the treatment of Alzheimer's disease, and compound (I) Can be used to strongly stimulate the Ml receptor. Therefore, the compound of the present invention is useful as (I) a therapeutic agent for Alzheimer's dementia.
  • the above starch powder was mixed and passed through a 60 mesh sieve, and then 25 Omg of this powder was placed in a No. 3 gelatin capsule to prepare a capsule.
  • Exo-1-azabicyclo [2,2,1] heptane-3-ol A solution of 0.50 g of dimethylformaside (10 ml) was cooled to 5 under a stream of nitrogen, and the sodium hydride (content 55%) was obtained. 0.21 g was added, and the mixture was stirred at room temperature for 30 minutes. Then, the reaction solution was cooled to 5 ° C, 1.04 g of 3,4-dichloro-15-phenylisoxazole was added, and the mixture was stirred at room temperature for 3 hours.
  • the reaction solution was poured into ice water (50 ml), extracted with ethyl acetate (50 ml), and 0.1N-hydrochloric acid (50 ml) was added to the ethyl acetate layer for extraction. Separate the aqueous layer, adjust the pH to 10 with sodium carbonate, and extract with ethyl acetate (50 ml). Then, the organic layer was dried using anhydrous magnesium sulfate. After the desiccant was removed by filtration, the solvent was distilled off under reduced pressure to obtain 1.04 g (73.1%) of a colorless and oily free product of the target substance.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Composé d'isoxarole répondant à la formule générale (I), ou son sel d'addition d'acide. Dans la formule (I), R1 représente hydrogène, halogène, alkyle inférieur ou cycloalkyle; R2 représente hydrogène, alkyle inférieur, cycloalkyle, un groupe phényle possédant éventuellement un ou plusieurs substituants sélectionnés dans le groupe de substituants A, ou un groupe hétérocyclique aromatique possédant éventuellement un ou plusieurs substituants sélectionnés dans le groupe de substituants A; ou R1 et R2, associés l'un à l'autre, représentent -CR?4 = CR5-CR6 = CR7-, où R4, R5, R6 et R7¿, identiques ou différents, représentent, indépendamment les uns des autres, hydrogène, halogène, alkyle inférieur, alcoxy inférieur, halométhyle, alkylamino inférieur, alcanoylamino inférieur, hydroxy, nitro ou amino. Le groupe de substituants A comprend alkyle inférieur, hydroxy, alcoxy inférieur, halogène, nitro, amino et alkylamino inférieur. Ledit composé a l'effet de traiter la démence, d'améliorer les fonctions cérébrales, et ainsi de suite.
PCT/JP1994/000201 1993-02-12 1994-02-10 Derive d'isoxazoleoxy Ceased WO1994018201A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU60105/94A AU6010594A (en) 1993-02-12 1994-02-10 Isoxazoleoxy derivative

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2402893 1993-02-12
JP5/24028 1993-02-12

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WO1994018201A1 true WO1994018201A1 (fr) 1994-08-18

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Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5605908A (en) * 1994-10-24 1997-02-25 Eli Lilly And Company Heterocyclic compounds and their use
US5646289A (en) * 1994-10-24 1997-07-08 Eli Lilly And Company Heterocyclic compounds and their preparation and use
US6194416B1 (en) 1994-10-24 2001-02-27 Eli Lilly And Company Heterocyclic compounds and their use
EP0900217A4 (fr) * 1996-04-23 2001-05-23 Lilly Co Eli Composes heterocycliques
EP0900218A4 (fr) * 1996-04-23 2001-05-23 Lilly Co Eli Composes heterocycliques
EP0900219A4 (fr) * 1996-04-23 2001-05-23 Lilly Co Eli Composes heterocycliques
US6743815B2 (en) 1998-08-07 2004-06-01 Chiron Corporation Estrogen receptor modulators
US7160876B2 (en) 2003-12-22 2007-01-09 Abbott Laboratories Fused bicycloheterocycle substituted quinuclidine derivatives
US7241773B2 (en) 2003-12-22 2007-07-10 Abbott Laboratories 3-quinuclidinyl heteroatom bridged biaryl derivatives
US7309699B2 (en) 2003-12-22 2007-12-18 Abbott Laboratories 3-Quinuclidinyl amino-substituted biaryl derivatives
US7655657B2 (en) 2003-12-22 2010-02-02 Abbott Laboratories Fused bicycloheterocycle substituted quinuclidine derivatives
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
US8236803B2 (en) 2002-09-04 2012-08-07 Novartis Ag Aza-bicycloalkyl ethers and their use as alpha7-nAChR agonists
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
US8759346B2 (en) 2005-12-16 2014-06-24 Novartis Ag Organic compounds
US8933090B2 (en) 2004-06-18 2015-01-13 Novartis Ag 1-aza-bicyclo[3.3.1]nonanes

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS63290878A (ja) * 1987-04-15 1988-11-28 ビーチャム・グループ・ピーエルシー 新規化合物、その製法及びそれを含む医薬組成物
JPH01299277A (ja) * 1988-05-24 1989-12-04 Sankyo Co Ltd イソオキサゾール化合物およびその用途

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS63290878A (ja) * 1987-04-15 1988-11-28 ビーチャム・グループ・ピーエルシー 新規化合物、その製法及びそれを含む医薬組成物
JPH01299277A (ja) * 1988-05-24 1989-12-04 Sankyo Co Ltd イソオキサゾール化合物およびその用途

Cited By (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5605908A (en) * 1994-10-24 1997-02-25 Eli Lilly And Company Heterocyclic compounds and their use
US5646289A (en) * 1994-10-24 1997-07-08 Eli Lilly And Company Heterocyclic compounds and their preparation and use
US5665745A (en) * 1994-10-24 1997-09-09 Eli Lilly And Company Heterocyclic compounds and their preparation and use
US5672709A (en) * 1994-10-24 1997-09-30 Eli Lilly And Company Heterocyclic compounds and their preparation and use
US5821370A (en) * 1994-10-24 1998-10-13 Eli Lilly And Company Heterocyclic compounds and their preparation and use
US5821371A (en) * 1994-10-24 1998-10-13 Eli Lilly And Comany Heterocyclic compounds and their preparation and use
US5929247A (en) * 1994-10-24 1999-07-27 Eli Lilly And Company Heterocyclic compounds and their preparation and use
US6194416B1 (en) 1994-10-24 2001-02-27 Eli Lilly And Company Heterocyclic compounds and their use
EP0900217A4 (fr) * 1996-04-23 2001-05-23 Lilly Co Eli Composes heterocycliques
EP0900218A4 (fr) * 1996-04-23 2001-05-23 Lilly Co Eli Composes heterocycliques
EP0900219A4 (fr) * 1996-04-23 2001-05-23 Lilly Co Eli Composes heterocycliques
US6743815B2 (en) 1998-08-07 2004-06-01 Chiron Corporation Estrogen receptor modulators
US6869969B2 (en) 1998-08-07 2005-03-22 Chiron Corporation Estrogen receptor modulators
US9849117B2 (en) 2002-09-04 2017-12-26 Novartis Ag Aza-bicycloalkyl ethers and their use as alpha7-nachr agonists
US8236803B2 (en) 2002-09-04 2012-08-07 Novartis Ag Aza-bicycloalkyl ethers and their use as alpha7-nAChR agonists
US9567343B2 (en) 2002-09-04 2017-02-14 Novartis Ag Aza-bicyloalkyl ethers and their use as alpha7-nachr agonists
US9012451B2 (en) 2002-09-04 2015-04-21 Novartis Ag Aza-bicycloalkyl ethers and their use as ALPHA7-nachr agonists
US7241773B2 (en) 2003-12-22 2007-07-10 Abbott Laboratories 3-quinuclidinyl heteroatom bridged biaryl derivatives
US7655657B2 (en) 2003-12-22 2010-02-02 Abbott Laboratories Fused bicycloheterocycle substituted quinuclidine derivatives
US7160876B2 (en) 2003-12-22 2007-01-09 Abbott Laboratories Fused bicycloheterocycle substituted quinuclidine derivatives
US7674794B2 (en) 2003-12-22 2010-03-09 Abbott Laboratories Fused bicycloheterocycle substituted quinuclidine derivatives
US7309699B2 (en) 2003-12-22 2007-12-18 Abbott Laboratories 3-Quinuclidinyl amino-substituted biaryl derivatives
US9475811B2 (en) 2004-06-18 2016-10-25 Novartis Ag 1-aza-bicyclo[3.3.1]nonanes
US8933090B2 (en) 2004-06-18 2015-01-13 Novartis Ag 1-aza-bicyclo[3.3.1]nonanes
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
US9657010B2 (en) 2004-07-14 2017-05-23 Novartis Ag Substituted quinuclidines as alpha 7-nicotinic acetylcholine receptor activity modulators
US8173667B2 (en) 2005-10-21 2012-05-08 Novartis Ag 1-aza-bicycloalkyl derivatives
US8759346B2 (en) 2005-12-16 2014-06-24 Novartis Ag Organic compounds
US8637517B2 (en) 2005-12-16 2014-01-28 Novartis Ag Organic compounds
US9206181B2 (en) 2005-12-16 2015-12-08 Novartis Ag 1-aza-bicyclo[3.3.1] non-4-yl)-[5-(1H-indol-5-yl)-heteroaryl]-amines as cholinergic ligands of the n-AChR for the treatment of psychotic and neurodegenerative disorders
US8048885B2 (en) 2005-12-16 2011-11-01 Novartis Ag Organic compounds

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