WO2006065788A2 - Nouveaux antagonistes du recepteur muscarinique de l'acetylcholine - Google Patents

Nouveaux antagonistes du recepteur muscarinique de l'acetylcholine Download PDF

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Publication number
WO2006065788A2
WO2006065788A2 PCT/US2005/045012 US2005045012W WO2006065788A2 WO 2006065788 A2 WO2006065788 A2 WO 2006065788A2 US 2005045012 W US2005045012 W US 2005045012W WO 2006065788 A2 WO2006065788 A2 WO 2006065788A2
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group
substituted
phenyl
cycloalkyl
alkyl
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PCT/US2005/045012
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English (en)
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WO2006065788A3 (fr
Inventor
Jakob Busch-Petersen
Roderick S. Davis
Wei Fu
Jian Jin
Dramane I. Laine
Michael R. Palovich
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Glaxo Group Limited
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Publication of WO2006065788A2 publication Critical patent/WO2006065788A2/fr
Publication of WO2006065788A3 publication Critical patent/WO2006065788A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • This invention relates to novel derivatives of cyclic amines, pharmaceutical compositions, processes for their preparation, and use thereof in treating muscarinic acetylcholine receptor mediated diseases.
  • Muscarinic acetylcholine receptors (mAChRs) belong to the superfamily of G- protein coupled receptors that have seven transmembrane domains. There are five subtypes of mAChRs, termed M-
  • Muscarinic acetylcholine receptors are widely distributed in vertebrate organs, and these receptors can mediate both inhibitory and excitatory actions. For example, in smooth muscle found in the airways, bladder and gastrointestinal tract, M3 mAChRs mediate contractile responses.
  • Muscarinic acetylcholine receptor dysfunction has been noted in a variety of different pathophysiological states. For instance, in asthma and chronic obstructive pulmonary disease (COPD), inflammatory conditions lead to loss of inhibitory M2 muscarinic acetylcholine autoreceptor function on parasympathetic nerves supplying the pulmonary smooth muscle, causing increased acetylcholine release following vagal nerve stimulation. This mAChR dysfunction results in airway hyperreactivity mediated by increased stimulation of M3 mAChRs ⁇ Costello, Evans, et al. 1999 72 /id ⁇ Minette,
  • Lammers et al. 1989 248 /id ⁇ .
  • inflammation of the gastrointestinal tract in inflammatory bowel disease (IBD) results in M3 mAChR-mediated hypermotility ⁇ Oprins,
  • This invention relates to compounds of Formula I
  • Y is S, O; or NR4
  • X is N, or CR5, provided that the number of N at the X value cannot exceed 2;
  • Z is N, or CR5, provided that the number N at the Z value cannot exceed 3;
  • N is an integer from O to 3;
  • R1 is selected from the group consisting of C-j-Cs branched or unbranched alkyl, C ⁇ -Cg cycloalkyl, C3-C8 cycloalkyl lower alkyl, C3-C8 alkenyl, unsubstituted or substituted phenyl, or unsubstituted or substituted phenyl C1-C3 lower alkyl; wherein, when substituted, a group is substituted by one or more radicals selected from the group consisting of C ⁇ -Cs alkoxy, halo, hydroxy, amino, cyano, trifluoromethyl, C-j-Cg branched or unbranched alkyl, C3-C8 cycloalkyl, C3-C8 cycl
  • T is selected from the group consisting of thiophene, furan, thiazole, isothiazole, pyrrole, imidazole, pyrazole and para-substituted phenyl which may be substituted by radicals selected from the group consisting of C1 -C3 alkoxy, halo, hydroxy, amino, trifluoromethyl, C-
  • R3 is selected from the group consisting of COR6, COOR6, OSO 2 R6, N(R7)SO 2 R6, CONR6R7, NR6R7, OCOR6, OCONR6R7, NHCOR6, N(R7)COR6, NHCOOR6 and NHCONR6R7;
  • R4 is selected from the group consisting of hydrogen, C1-C3 alkyl and allyl
  • R5 is selected from the group consisting of hydrogen, C1 -C3 alkyl, C1-C3 alkenyl, , halo, NR4, OR4, CN, NO 2 , and trifluoromethyl
  • R6 is selected from the group consisting of substituted or unsubstituted Ci-Cg branched or unbranched alkyl, C3-C12 cycloalkyl, C3-C-12 cycloalkenyl, C3-C3 cycloalkyl lower alkyl, C3-C-8 alkenyl, phenyl, and phenyl C1-C3 lower alkyl wherein, when substituted, a group is substituted by one or more radicals selected from the group consisting of C-1-C3 alkoxy, halo, hydroxy, amino, cyano, nitro, trifluoromethyl, and C1-C3 branched
  • the present invention includes all hydrates, solvates, complexes and prodrugs of the compounds of this invention.
  • Prodrugs are any covalently bonded compounds that release the active parent drug according to Formula I in vivo. If a chiral center or another form of an isomeric center is present in a compound of the present invention, all forms of such isomer or isomers, including enantiomers and diastereomers, are intended to be covered herein.
  • Inventive compounds containing a chiral center may be used as a racemic mixture, an enantiomerically enriched mixture, or the racemic mixture may be separated using well-known techniques and an individual enantiomer may be used alone.
  • C-i .Cs alky and "C- ⁇ Cg alkyl” is used herein includes both straight or branched chain radicals of 1 to 6 or 8 carbon atoms. By example this term includes, but is not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, octyl and the like. "Lower alkyl” has the same meaning as C- ⁇ Cg alkyl.
  • C-] .Cs alkoxy includes straight and branched chain radicals of the likes of
  • C3-C8-cycloalkyl as applied herein is meant to include substituted and unsubstituted cyclopropane, cyclobutane, cyclopentane and cyclohexane, and the like.
  • Halogen or “halo” means F, Cl, Br, and I.
  • the preferred compounds of Formula I include those compounds wherein,
  • Y is S, O; or NR4
  • X is N, or CR5, provided that the number of N at the X value cannot exceed 2;
  • Z is N, or CR5, provided that the number of N at the Z position cannot exceed 3;
  • N is an integer from 0-3;
  • R1 is selected from the group consisting of C-j -C ⁇ branched or unbranched alkyl, C3-C-8 cycloalkyl, C3-C8 cycloalkyl lower alkyl, C3-C8 alkenyl, unsubstituted or substituted phenyl, or unsubstituted or substituted phenyl C1-C3 lower alkyl; wherein, when substituted, a group is substituted by one or more radicals selected from the group consisting of C-] -Cs alkoxy, halo, hydroxy, amino, cyano, trifluoromethyl, C-] -Cs branched or unbranched alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl lower alkyl, phenyl and phenyl
  • T is selected from the group consisting of thiophene, furan, thiazole, isothiazole, pyrrole, imidazole, pyrazole or para-substituted phenyl which may be substituted by radicals selected from the group consisting of C-1-C3 alkoxy, halo, hydroxy, amino, trifluoromethyl, C1-C4 branched or unbranched alkyl, C3-C-8 cycloalkyl, C3-C8 cycloalkyl lower alkyl and phenyl;
  • R3 is selected from the group consisting of COR6, COOR6, OSO 2 R6, N(R7)SO 2 R6,
  • R5 is selected from the group consisting of hydrogen, C1-C3 alkyl, C1 -C3 alkenyl, , halo, NR4, 0R4, CN, NO 2 , and trifluoromethyl
  • R6 is selected from the group consisting of substituted or unsubstituted C-
  • Y is S, or O;
  • X is CR5;
  • Z is CR5;
  • n is 1 or 2;
  • R1 is selected from the group consisting of unsubstituted or substituted phenyl wherein, when substituted, a group is substituted by one or more radicals selected from the group consisting of C-] -Cs alkoxy, halo, hydroxy, amino, cyano, trifluoromethyl, C-
  • T is selected from the group consisting of thiophene, furan, or para-substituted phenyl which may be substituted by radicals selected from the group consisting of C-1-C3 alkoxy, halo, hydroxy, amino, trifluoromethyl, C1 -C4 branched or unbranched alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl lower alkyl and phenyl.
  • R3 is selected from the group consisting of COOR6, OSO 2 R6, N(R7)SO 2 R6, and CONR6R7;
  • R4 is selected from the group consisting of hydrogen, C1-C3 alkyl and allyl
  • R5 is selected from the group consisting of hydrogen, C1-C3 alkyl, C1 -C3 alkenyl, , halo, NR4, OR4, CN, NO 2 , and trifluoromethyl
  • R6 is selected from the group consisting of substituted or unsubstituted C- j -Cs branched or unbranched alkyl, C3-C12 cycloalkyl, 03-0-12 cycloalkenyl, C3-C8 cycloalkyl lower alkyl, C3-C8 alkenyl, phenyl, or phenyl 01 -03 lower alkyl wherein, when substituted, a yi ⁇ u ⁇ is suusiuuieu ⁇ y one or more radicals selected from the group consisting of C1-C3 alkoxy, halo, hydroxy, amino, cyano, nitro, trifluoromethyl, and C1-C3 branched or unbranched alkyl;
  • R7 is selected from the group consisting of hydrogen, C1 -C3 alkyl and allyl. Even more preferred are those compounds where:
  • Y is S;
  • X is CR5;
  • Z is CR5;
  • N is i ;
  • R1 is selected from the group consisting of unsubstituted or substituted phenyl wherein, when substituted, a group is substituted at the meta or para position by one radical selected from the group consisting of C1-C3 alkoxy, halo, hydroxy, amino, cyano, nitro, trifluoromethyl, and C1 -C3 branched or unbranched alkyl;
  • T is of thiophene or para-substituted phenyl
  • R3 is selected from the group consisting of COOR6, OSO 2 R6, and N(R7)SO 2 R6;
  • R4 is hydrogen;
  • R5 is hydrogen;
  • R6 is selected from the group consisting of substituted or unsubstituted C-
  • the preferred compounds are selected from the group consisting of: ⁇ /- ⁇ [(4- ⁇ [(1 -methylethyl)amino]sulfonyl ⁇ phenyl)amino]carbonyl ⁇ - ⁇ /-[(2-methylimidazo[2,1- £][1 ,3]thiazol-6-yl)methyl]-L-tyrosinamide; Methyl 5-( ⁇ [((1 S)-1 -[(4-hydroxyphenyl)methyl]-2- ⁇ [(2-methylimidazo[2,1 -b][ ⁇ ,3]thiazol-6- yl)methyl]amino ⁇ -2-oxoethyl)amino]carbonyl ⁇ amino)-2-thiophenecarboxylate; Cyclohexyl 5-( ⁇ [((1 S)-1-( ⁇ 4-[(1 ,1-dimethylethyl)oxy]phenyl ⁇ methyl)-2- ⁇ [(2- methylimidazo[2,1
  • the compounds of Formula (I) may be obtained by applying synthetic procedures, some of which are illustrated in the Schemes below.
  • the synthesis provided for these Schemes is applicable for producing compounds of Formula (I) having a variety of different R1 , R3, R4, R5 and R6, which are reacted, employing substituents which are suitable protected, to achieve compatibility with the reactions outlined herein. Subsequent deprotection, in those cases, then affords compounds of the nature generally disclosed. While some Schemes are shown with specific compounds, this is merely for illustration purpose only.
  • Resin-bound amine 4 was prepared by reductive amination of 2,6-dimethoxy-4-polystyrenebenzyloxy- benzaldehyde (DMHB resin) with amine 3. Reaction of 4 with Fmoc-protected amino acid, followed by removal of the protecting group, provided resin-bound intermediate 6. The amines were coupled with resin-bound intermediate 6 to afford the corresponding resin- bound ureas 7. The resin was then cleaved by 50% trifluoroacetic acid in dichloromethane to afford targeted compounds 8 (Scheme 1 ).
  • DMHB resin 2,6-dimethoxy-4-polystyrenebenzyloxy- benzaldehyde
  • 6-(Chloromethyl)-2-methylimidazo[2,1 -d][1 ,3]thiazole 1 (4.47 g, 23.82 mmol) was dissolved in DMSO (50 mL). Sodium azide (1.55 g, 23.82 mmol) was added. The reaction mixture was heated to 65 0 C overnight. Water (200 mL) was added after the reaction mixture was cooled to room temperature. The mixture was extracted with ethyl acetate (3x 150 mL).
  • the above resin 5 (8.68 mmol) was treated with 100 mL of 20% piperidine in anhydrous 1 -methyl-2-pyrrolidinone solution. After the mixture was shaken at room temperature for 15 min, the solution was drained and another 100 mL of 20% piperidine in anhydrous 1 -methyl-2-pyrrolidinone solution was added. The mixture was shaken at rt for another 15 min. The solution was drained and the resin was washed with DMF (3 x 50 mL), CH2Cl2/MeOH (1 :1 , 3 x 50 mL) and MeOH (3 x 50 mL). The resulting resin 6 was dried in vacuum oven at 35 0 C for 24 h.
  • the resin was washed with CH2CI2 (3 x 10 mL), C ⁇ C ⁇ /MeOH (1 :1 , 3 x 10 mL), MeOH (3 x 10 mL) and CH2CI2 (3 x 1OmL). The resulting resin was dried in vacuum oven at 35 0 C for 24 h.
  • the dry resin was treated with 2 mL of 50% trifluoroacetic acid in dichloromethane at rt for 2h. After the cleavage solution was collected, the resin was treated with another 2 mL of 50% trifluoroacetic acid in dichloromethane at rt for 10min. The combined cleavage solutions were concentrated in vacuo.
  • inhibitory effects of compounds at the M3 mAChR of the present invention are determined by the following in vitro and in vivo assays:
  • a CHO (Chinese hamster ovary) cell line stably expressing the human M3 muscarinic acetylcholine receptor is grown in DMEM plus 10% FBS, 2 mM Glutamine and 200 ug/ml G418. Cells are detached for maintenance and for plating in preparation for assays using either enzymatic or ion chelation methods.
  • the day before the FLIPR (fluorometric imaging plate reader) assay cells are detached, resuspended, counted, and plated to give 20,000 cells per 384 well in a 50 ul volume.
  • the assay plates are black clear bottom plates, Becton Dickinson catalog number 35 3962.
  • the assay is run the next day.
  • media are aspirated, and cells are washed with 1x assay buffer (145mM NaCI, 2.5mM KCI, 1 OmM glucose, 1OmM HEPES, 1.2 mM MgCI 2 , 2.5mM CaCI 2 , 2.5mM probenecid (pH 7.4.)
  • Cells are then incubated with 5OuI of Fluo-3 dye (4uM in assay buffer) for 60 - 90 minutes at 37 degrees C.
  • the calcium- sensitive dye allows cells to exhibit an increase in fluorescence upon response to ligand via release of calcium from intracellular calcium stores.
  • Test compounds and antagonists are added in 25 ul volume, and plates are incubated at 37 degrees C for 5 -30 minutes. A second addition is then made to each well, this time with the agonist challenge, acetylcholine. It is added in 25 ul volume on the FLIPR instrument. Calcium responses are measured by changes in fluorescent units.
  • acetylcholine ligand is added at an EC 80 concentration, and the antagonist IC 50 can then be determined using dose response dilution curves.
  • the control antagonist used with M3 is atropine.
  • mAChRs expressed on CHO cells were analyzed by monitoring receptor- activated calcium mobilization as previously described .
  • CHO cells stably expressing M3 mAChRs were plated in 96 well black wall/clear bottom plates. After 18 to 24 hours, media was aspirated and replaced with 100 ⁇ l of load media (EMEM with Earl's salts, 0.1% RIA-grade BSA (Sigma, St. Louis MO), and 4 ⁇ M Fluo-3-acetoxymethyl ester fluorescent indicator dye (Fluo-3 AM, Molecular Probes, Eugene, OR) and incubated 1 hr at 37° C.
  • load media EMEM with Earl's salts, 0.1% RIA-grade BSA (Sigma, St. Louis MO
  • Fluo-3-acetoxymethyl ester fluorescent indicator dye Fluo-3 AM, Molecular Probes, Eugene, OR
  • the dye-containing media was then aspirated, replaced with fresh media (without Fluo-3 AM), and cells were incubated for 10 minutes at 37° C. Cells were then washed 3 times and incubated for 10 minutes at 37° C in 100 ⁇ l of assay buffer (0.1 % gelatin (Sigma), 120 mM NaCI, 4.6 mM KCI, 1 mM KH 2 PO 4 , 25 mM NaH CO 3 , 1.0 mM
  • mice were then challenged with an aerosol of methacholine (10 mg/ml) for 2 minutes. Penh was recorded continuously for 7 min starting at the inception of the methacholine aerosol, and continuing for 5 minutes afterward. Data for each mouse were analyzed and plotted by using GraphPad PRISM software.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

L'invention concerne des antagonistes du récepteur muscarinique de l'acétylcholine, et des méthodes d'utilisation des antagonistes.
PCT/US2005/045012 2004-12-13 2005-12-13 Nouveaux antagonistes du recepteur muscarinique de l'acetylcholine WO2006065788A2 (fr)

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Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006065755A2 (fr) * 2004-12-13 2006-06-22 Glaxo Group Limited Sels d'ammonium quaternaire d'amines heteroaromatiques fusionnees utilises comme nouveaux antagonistes du recepteur de l'acetylcholine muscarinique
US7276521B2 (en) 2003-10-14 2007-10-02 Glaxo Group Limited Muscarinic acetylcholine receptor antagonists
US7384946B2 (en) 2004-03-17 2008-06-10 Glaxo Group Limited M3 muscarinic acetylcholine receptor antagonists
US7439255B2 (en) 2003-11-04 2008-10-21 Glaxo Group Limited Muscarinic acetylcholine receptor antagonists
US7488827B2 (en) 2004-04-27 2009-02-10 Glaxo Group Limited Muscarinic acetylcholine receptor antagonists
US7495010B2 (en) 2003-07-17 2009-02-24 Glaxo Group Limited Muscarinic acetylcholine receptor antagonists
US7507747B2 (en) 2003-10-17 2009-03-24 Glaxo Group Limited Muscarinic acetylcholine receptor antagonists
US7598267B2 (en) 2004-05-13 2009-10-06 Glaxo Group Limited Muscarinic acetylcholine receptor antagonists
US7767691B2 (en) 2005-08-18 2010-08-03 Glaxo Group Limited Muscarinic acetylcholine receptor antagonists containing an azoniabiocyclo[2.2.1] heptane ring system
WO2010094643A1 (fr) 2009-02-17 2010-08-26 Glaxo Group Limited Dérivés de quinoline et applications associées dans la rhinite et l'urticaire
US7932247B2 (en) 2004-11-15 2011-04-26 Glaxo Group Limited M3 muscarinic acetylcholine receptor antagonists
WO2011051672A1 (fr) * 2009-10-28 2011-05-05 Vantia Limited Dérivés azaindole
US8067408B2 (en) 2008-02-06 2011-11-29 Glaxo Group Limited Dual pharmacophores—PDE4-muscarinic antagonistics
US8071588B2 (en) 2008-02-06 2011-12-06 Glaxo Group Limited Dual pharmacophores—PDE4-muscarinic antagonistics
US8084449B2 (en) 2008-02-06 2011-12-27 Glaxo Group Limited Dual pharmacophores—PDE4-muscarinic antagonistics
US8188272B2 (en) 2007-03-21 2012-05-29 Bristol-Myers Squibb Company Fused heterocyclic compounds useful as kinase modulators
US8476430B2 (en) 2008-07-24 2013-07-02 Bristol-Myers Squibb Company Fused heterocyclic compounds useful as kinase modulators
US8940736B2 (en) 2012-07-13 2015-01-27 Bristol-Myers Squibb Company Imidazotriazinecarbonitriles useful as kinase inhibitors

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US6657064B2 (en) * 1999-10-08 2003-12-02 Gruenenthal Gmbh Bicyclic imidazo-5-yl-amine derivatives

Patent Citations (1)

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Publication number Priority date Publication date Assignee Title
US6657064B2 (en) * 1999-10-08 2003-12-02 Gruenenthal Gmbh Bicyclic imidazo-5-yl-amine derivatives

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US7495010B2 (en) 2003-07-17 2009-02-24 Glaxo Group Limited Muscarinic acetylcholine receptor antagonists
US7579361B2 (en) 2003-10-14 2009-08-25 Glaxo Group Limited Muscarinic acetylcholine receptor antagonists
US7276521B2 (en) 2003-10-14 2007-10-02 Glaxo Group Limited Muscarinic acetylcholine receptor antagonists
US7576096B2 (en) 2003-10-14 2009-08-18 Glaxo Group Limited Muscarinic acetylcholine receptor antagonists
US7507747B2 (en) 2003-10-17 2009-03-24 Glaxo Group Limited Muscarinic acetylcholine receptor antagonists
US7439255B2 (en) 2003-11-04 2008-10-21 Glaxo Group Limited Muscarinic acetylcholine receptor antagonists
US7563803B2 (en) 2003-11-04 2009-07-21 Glaxo Group Limited M3 muscarinic acetylcholine receptor antagonists
US7906531B2 (en) 2003-11-04 2011-03-15 Glaxo Group Limited M3 muscarinic acetylcholine receptor antagonists
US7384946B2 (en) 2004-03-17 2008-06-10 Glaxo Group Limited M3 muscarinic acetylcholine receptor antagonists
US7488827B2 (en) 2004-04-27 2009-02-10 Glaxo Group Limited Muscarinic acetylcholine receptor antagonists
US7498440B2 (en) 2004-04-27 2009-03-03 Glaxo Group Limited Muscarinic acetylcholine receptor antagonists
US8183257B2 (en) 2004-04-27 2012-05-22 Glaxo Group Limited Muscarinic acetylcholine receptor antagonists
US9144571B2 (en) 2004-04-27 2015-09-29 Glaxo Group Limited Muscarinic acetylcholine receptor antagonists
US9045469B2 (en) 2004-04-27 2015-06-02 Glaxo Group Limited Muscarinic acetylcholine receptor antagonists
US8853404B2 (en) 2004-04-27 2014-10-07 Glaxo Group Limited Muscarinic acetylcholine receptor antagonists
US8575347B2 (en) 2004-04-27 2013-11-05 Glaxo Group Limited Muscarinic acetylcholine receptor antagonists
US8309572B2 (en) 2004-04-27 2012-11-13 Glaxo Group Limited Muscarinic acetylcholine receptor antagonists
US7598267B2 (en) 2004-05-13 2009-10-06 Glaxo Group Limited Muscarinic acetylcholine receptor antagonists
US7932247B2 (en) 2004-11-15 2011-04-26 Glaxo Group Limited M3 muscarinic acetylcholine receptor antagonists
WO2006065755A2 (fr) * 2004-12-13 2006-06-22 Glaxo Group Limited Sels d'ammonium quaternaire d'amines heteroaromatiques fusionnees utilises comme nouveaux antagonistes du recepteur de l'acetylcholine muscarinique
WO2006065755A3 (fr) * 2004-12-13 2006-10-12 Glaxo Group Ltd Sels d'ammonium quaternaire d'amines heteroaromatiques fusionnees utilises comme nouveaux antagonistes du recepteur de l'acetylcholine muscarinique
US7767691B2 (en) 2005-08-18 2010-08-03 Glaxo Group Limited Muscarinic acetylcholine receptor antagonists containing an azoniabiocyclo[2.2.1] heptane ring system
US8188272B2 (en) 2007-03-21 2012-05-29 Bristol-Myers Squibb Company Fused heterocyclic compounds useful as kinase modulators
US8067408B2 (en) 2008-02-06 2011-11-29 Glaxo Group Limited Dual pharmacophores—PDE4-muscarinic antagonistics
US8071588B2 (en) 2008-02-06 2011-12-06 Glaxo Group Limited Dual pharmacophores—PDE4-muscarinic antagonistics
US8084449B2 (en) 2008-02-06 2011-12-27 Glaxo Group Limited Dual pharmacophores—PDE4-muscarinic antagonistics
US8476430B2 (en) 2008-07-24 2013-07-02 Bristol-Myers Squibb Company Fused heterocyclic compounds useful as kinase modulators
WO2010094643A1 (fr) 2009-02-17 2010-08-26 Glaxo Group Limited Dérivés de quinoline et applications associées dans la rhinite et l'urticaire
WO2011051672A1 (fr) * 2009-10-28 2011-05-05 Vantia Limited Dérivés azaindole
US8940736B2 (en) 2012-07-13 2015-01-27 Bristol-Myers Squibb Company Imidazotriazinecarbonitriles useful as kinase inhibitors
US9273057B2 (en) 2012-07-13 2016-03-01 Bristol-Myers Squibb Company Imidazotriazinecarbonitriles useful as kinase inhibitors
US9556178B2 (en) 2012-07-13 2017-01-31 Bristol-Myers Squibb Company Imidazotriazinecarbonitriles useful as kinase inhibitors

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