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WO2006065755A2 - Sels d'ammonium quaternaire d'amines heteroaromatiques fusionnees utilises comme nouveaux antagonistes du recepteur de l'acetylcholine muscarinique - Google Patents

Sels d'ammonium quaternaire d'amines heteroaromatiques fusionnees utilises comme nouveaux antagonistes du recepteur de l'acetylcholine muscarinique Download PDF

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Publication number
WO2006065755A2
WO2006065755A2 PCT/US2005/044951 US2005044951W WO2006065755A2 WO 2006065755 A2 WO2006065755 A2 WO 2006065755A2 US 2005044951 W US2005044951 W US 2005044951W WO 2006065755 A2 WO2006065755 A2 WO 2006065755A2
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methyl
phenyl
group
carbonyl
amino
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PCT/US2005/044951
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English (en)
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WO2006065755A3 (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 WO2006065755A2 publication Critical patent/WO2006065755A2/fr
Publication of WO2006065755A3 publication Critical patent/WO2006065755A3/fr

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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
    • C07D471/02—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 two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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 receptors 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-j -M5, and each is the product of a distinct gene. Each of these five subtypes displays unique pharmacological properties.
  • 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 of N at the Z value cannot exceed 3;
  • N is and integer from 0 to 3;
  • a " is selected from the group consisting of halo, CF 3 COO ' , mesylate, tosylate, and any other pharmaceutically acceptable counter ion;
  • R1 is selected from the group consisting of C ⁇ -Cs branched or unbranched alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl lower alkyl, C3-C8 alkenyl, unsubstituted or substituted phenyl, or unsubstituted and 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-J -Cg alkoxy, halo, hydroxy, amino, cyano, trifluoromethyl, C-] -Cg 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 and para-substituted phenyl which may be substituted by one or more radical selected from the group consisting of C1-C3 alkoxy, halo, hydroxy, amino, trifluoromethyl, C1-C4 branched or unbranched alkyl, C3-C8 cycloalkyl, and C3-C8 cycloalkyl lower alkyl or phenyl;
  • R2 is selected from the group consisting of C-j -C3 branched or unbranched alkyl, C3-C8 cycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted naphthyl and 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-
  • R4 is selected from the group consisting of hydrogen, C1 -C3 alkyl and allyl
  • R5 is selected from the following groupconsisting 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- ⁇ -Cs branched or unbranched alkyl, C3-C12 cycloalkyl, C3-C-12 cycloalkenyl, C3-C8 cycloalkyl lower alkyl, C3-C8 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 C1-C3 alkoxy, halo, hydroxy, amino, cyano, nitro, trifluoromethyl, and C-1 -C3 branched or unbranched alkyl; and
  • R7 is selected from the group consisting of: hydrogen, C1-C4 alkyl and allyl.
  • 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.
  • this term includes, but is not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, te/t-butyl, pentyl, hexyl, heptyl, octyl and the like.
  • “Lower alkyl” has the same meaning as C ⁇ .Cs alkyl.
  • C-] .Cs alkoxy includes straight and branched chain radicals of the likes of
  • C3-Cs-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 value cannot exceed 3;
  • n is an integer from 0 to 3;
  • a " is selected from the group consisting of halo, CF 3 COO " , mesylate, tosylate, or any other pharmaceutically acceptable counter ion;
  • R1 is selected from the group consisting of C-
  • 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 C-
  • R2 is selected from the group consisting of C-] -Cs branched or unbranched alkyl, C3-C8 cycloalkyl, unsubstituted or substituted phenyl, unsubstituted or substituted naphthyl and 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 C1 -C8 alkoxy, halo, hydroxy, amino, cyano, trifluoromethyl, and 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
  • 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,
  • R6 is selected from the group consisting of substituted or unsubstituted C- ) -CQ branched or unbranched alkyl, C3-C12 cycloalkyl, C3-C-12 cycloalkenyl, C3-C8 cycloalkyl lower alkyl, C3-C8 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 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-C4 alkyl and allyl.
  • Y is S or O
  • X is CR5
  • Z is CR5
  • N is 1 or 2;
  • a " is selected from the group consisting of halo, CF 3 COO ' , mesylate, tosylate, and any other pharmaceutically acceptable counter ion;
  • 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 ⁇ -Cg alkoxy, halo, hydroxy, amino, cyano, trifluoromethyl, C-
  • T is selected from the group consisting of thiophene, furan, and para-substituted phenyl which may be substituted by radicals selected from the group consisting of C1-C3 alkoxy, halo, hydroxy, amino, trifluoromethyl, C1 -C4 branched or unbranched alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl lower alkyl and phenyl;
  • R2 is selected from the group consisting of C-
  • R3 is selected from the group consisting of COOR6, OSO 2 R6, N(R7)SO 2 R6, and
  • 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-
  • R7 is selected from the group consisting of hydrogen, C1 -C3 alkyl and allyl.
  • Y is S;
  • X is CR5;
  • Z is CR5;
  • N is 1 ;
  • a " is selected from the group consisting of halo, CF 3 COO " , mesylate, tosylate, and any other pharmaceutically acceptable counter ion;
  • 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 C- ⁇ -C3 alkoxy, halo, hydroxy, amino, cyano, nitro, trifluoromethyl, and C1-C3 branched or unbranched alkyl;
  • T is selected from thiophene or para-substituted phenyl
  • R2 is selected from the group consisting of C-
  • 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:
  • 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, which were treated with alkyl halides to form the corresponding quaternary ammonium salts. The resin was then cleaved by 50% trifluoroacetic acid in dichloromethane to afford targeted compounds 8 (Scheme 1 ). Scheme 2 and 3 showed the synthesis of formula 8 compounds using solution phase synthesis. The sequence and reaction conditions are similar.
  • N,N,N',N'-tetramethyluronium DMF, rt; b) bromethyl naphthalene, acetonitrile, chloroform, 170 0 C; c) trifluoroacetic acid in dichloromethane, rt; d) cyclohexyl 5-amino-2-thiophenecarboxylate, 4- nitrobenzene chloroformate, diisopropylethylamine, N,N-dimethyl formamide, dichloromethane, rt.
  • 6-(Chloromethyl)-2-methylimidazo[2,1-b][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_), CH 2 CI 2 /Me0H (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.
  • N, N 1 - Dimethylaminopyridine (652 mg, 5.33 mmol) , triethyl amine(4.47 mL, 32 mmol) and cyclohexanol (2.54 mL, 24 mmol) were added to reaction mixture and stirred at room temperature overnight.
  • the reaction mixture was filtered through a pad of silica gel (250 g), eluting with methylene chloride.
  • the crude cyclohexyl 5-nitro-2-thiophenecarboxylate was obtained after concentration, which was used in the next step without further purification.
  • inhibitory effects of compounds at the M3 mAChR of the present invention are determined by the following in vitro and in vivo assays:
  • 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 8 O 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. The dye-containing media was then aspirated, replaced with fresh media
  • Mice were pretreated with 50 ⁇ l of compound (0.003-10 ⁇ g/mouse) in 50 ⁇ l of vehicle (10% DMSO) intranasally, and were then placed in the plethysmography chamber. Once in the chamber, the mice were allowed to equilibrate for 10 min before taking a baseline Penh measurement for 5 minutes.
  • 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)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

L'invention concerne de nouveaux dérivés d'amines cycliques, des compositions pharmaceutiques, des procédés pour leur préparation ainsi que leur utilisation dans le traitement de maladies médiées par le récepteur de l'acétylcholine muscarinique.
PCT/US2005/044951 2004-12-13 2005-12-13 Sels d'ammonium quaternaire d'amines heteroaromatiques fusionnees utilises comme nouveaux antagonistes du recepteur de l'acetylcholine muscarinique WO2006065755A2 (fr)

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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
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
WO2013158597A1 (fr) * 2012-04-16 2013-10-24 Allergan, Inc. Dérivés de (2-ureidoacétamido)alkyle utilisés en tant que modulateurs du récepteur à peptide formylé 2
US8940736B2 (en) 2012-07-13 2015-01-27 Bristol-Myers Squibb Company Imidazotriazinecarbonitriles useful as kinase inhibitors
US9850264B2 (en) 2013-03-06 2017-12-26 Allergan, Inc. Use of agonists of formyl peptide receptor 2 for treating ocular inflammatory diseases
US10434112B2 (en) 2013-03-06 2019-10-08 Allergan, Inc. Use of agonists of formyl peptide receptor 2 for treating dermatological diseases
US10993931B2 (en) 2011-10-26 2021-05-04 Allergan, Inc. Amide derivatives of N-urea substituted amino acids as formyl peptide receptor like-1 (FPRL-1) receptor modulators

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Publication number Priority date Publication date Assignee Title
WO2006065788A2 (fr) * 2004-12-13 2006-06-22 Glaxo Group Limited Nouveaux antagonistes du recepteur muscarinique de l'acetylcholine

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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
US7906531B2 (en) 2003-11-04 2011-03-15 Glaxo Group Limited M3 muscarinic acetylcholine receptor antagonists
US7563803B2 (en) 2003-11-04 2009-07-21 Glaxo Group Limited M3 muscarinic acetylcholine receptor antagonists
US7384946B2 (en) 2004-03-17 2008-06-10 Glaxo Group Limited M3 muscarinic acetylcholine receptor antagonists
US8183257B2 (en) 2004-04-27 2012-05-22 Glaxo Group Limited Muscarinic acetylcholine receptor antagonists
US8575347B2 (en) 2004-04-27 2013-11-05 Glaxo Group Limited Muscarinic acetylcholine receptor antagonists
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US7498440B2 (en) 2004-04-27 2009-03-03 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
US7488827B2 (en) 2004-04-27 2009-02-10 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
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
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
US8067408B2 (en) 2008-02-06 2011-11-29 Glaxo Group Limited Dual pharmacophores—PDE4-muscarinic antagonistics
WO2010094643A1 (fr) 2009-02-17 2010-08-26 Glaxo Group Limited Dérivés de quinoline et applications associées dans la rhinite et l'urticaire
US10993931B2 (en) 2011-10-26 2021-05-04 Allergan, Inc. Amide derivatives of N-urea substituted amino acids as formyl peptide receptor like-1 (FPRL-1) receptor modulators
US9670150B2 (en) 2012-04-16 2017-06-06 Allergan, Inc. (2-ureidoacetamido)alkyl derivatives as formyl peptide receptor 2 modulators
JP2015520130A (ja) * 2012-04-16 2015-07-16 アラーガン、インコーポレイテッドＡｌｌｅｒｇａｎ，Ｉｎｃｏｒｐｏｒａｔｅｄ ホルミルペプチド受容体２調節物質としての（２−ウレイドアセトアミド）アルキル誘導体
WO2013158597A1 (fr) * 2012-04-16 2013-10-24 Allergan, Inc. Dérivés de (2-ureidoacétamido)alkyle utilisés en tant que modulateurs du récepteur à peptide formylé 2
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
US8940736B2 (en) 2012-07-13 2015-01-27 Bristol-Myers Squibb Company Imidazotriazinecarbonitriles useful as kinase inhibitors
US9850264B2 (en) 2013-03-06 2017-12-26 Allergan, Inc. Use of agonists of formyl peptide receptor 2 for treating ocular inflammatory diseases
US10208071B2 (en) 2013-03-06 2019-02-19 Allergan, Inc. Use of agonists of formyl peptide receptor 2 for treating ocular inflammatory diseases
US10434112B2 (en) 2013-03-06 2019-10-08 Allergan, Inc. Use of agonists of formyl peptide receptor 2 for treating dermatological diseases
US10899780B2 (en) 2013-03-06 2021-01-26 Allergan, Inc. Use of agonists of formyl peptide receptor 2 for treating ocular inflammatory diseases

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