WO2007090853A1 - Enantiomères de composes d'amino pyrimidine destinés à traiter des troubles inflammatoires - Google Patents

Enantiomères de composes d'amino pyrimidine destinés à traiter des troubles inflammatoires Download PDF

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Publication number
WO2007090853A1
WO2007090853A1 PCT/EP2007/051183 EP2007051183W WO2007090853A1 WO 2007090853 A1 WO2007090853 A1 WO 2007090853A1 EP 2007051183 W EP2007051183 W EP 2007051183W WO 2007090853 A1 WO2007090853 A1 WO 2007090853A1
Authority
WO
WIPO (PCT)
Prior art keywords
pyrrolidin
furo
pyrimidin
benzo
methylamino
Prior art date
Application number
PCT/EP2007/051183
Other languages
English (en)
Inventor
Alison Reid
Francis Wilson
Hazel Dyke
Steve Price
Sue Cramp
Original Assignee
Cellzome (Uk) 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
Priority claimed from EP06101510A external-priority patent/EP1829879A1/fr
Priority claimed from EP06114490A external-priority patent/EP1860108A1/fr
Application filed by Cellzome (Uk) Ltd. filed Critical Cellzome (Uk) Ltd.
Publication of WO2007090853A1 publication Critical patent/WO2007090853A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the H4 receptor is expressed mainly in cells of the hemopoietic lineage, especially mast cells, eosinophils and basophils (Oda T et al., J Biol Chem. 2000 Nov 24; 275(47):36781-
  • H4 is also implicated in histamine-induced interleukin-16 release from human CD8+ T cells (Gantner F et al., J Pharmacol Exp Ther. 2002 Oct; 303(l):300-7), in leukotriene B4 production and mast cell dependent neutrophil recruitment (Takeshita K et al., J Pharmacol Exp Ther. 2003 Dec; 307(3): 1072-8). All these data indicate that the histamine H4 receptor may play a role in the inflammatory response.
  • JNJ7777120 An indole amide, JNJ7777120, has been recently described as a potent and selective Histamine H4 receptor antagonist, (Ki 4.5 nM. pA2 8.1. Equipotent against human, mouse and rat receptors. >1000-fold selectivity over Hl, H2, or H3 receptor and no cross binding against 50 other targets) (Thurmond RL et al., J Pharmacol Exp Ther. 2004 Apr; 309(l):404-13).
  • JNJ7777120 in vitro, blocks histamine-induced chemotaxis and calcium influx in mouse mast cells, and in vivo histamine induced migration of tracheal mast cells from the connective tissue to the epithelium in mice. JNJ7777120 reduces infiltration in a mouse zymosan- induced peritonitis model indicating a role of the histamine H4 receptor in an inflammatory process in vivo.
  • Inflammation herein refers to the response that develops as a consequence of histamine release that can be caused by immunological and non-immunological stimuli. Inflammation can be due to any one or a plurality of conditions including, but not limited to, allergy, allergic rhinitis and asthma. In terms of the development of the disorder the inflammatory conditions include, but are not limited to, acute inflammation, allergic inflammation and chronic inflammation.
  • R 1 and R 2 are independently selected from the group consisting of H, -C(O)CH 3 ,
  • R 5 is H, F, Cl, Br, CN, CH 3 , CF 3 , OH, OCH 3 , or OCF 3 .
  • R 3 and R 4 are H, R 3 and R 4 are CH 3 or when R 3 and R 4 are different one of them is H.
  • R 5 is Cl
  • isomers can be separated by methods well known in the art, e.g. by liquid chromatography. Same applies for enantiomers by using e.g. chiral stationary phases.
  • enantiomers may be isolated by converting them into diastereomers, i.e. coupling with an enantiomerically pure auxiliary compound, subsequent separation of the resulting diastereomers and cleavage of the auxiliary residue.
  • any enantiomer of a compound of formula (I) may be obtained from stereoselective synthesis using optically pure starting materials.
  • pharmaceutically acceptable means approved by a regulatory agency such as the EMEA (Europe) and/or the FDA (US) and/or any other national regulatory agency for use in animals, preferably in humans.
  • the invention includes all salts of the compounds according to the invention which, owing to low physiological compatibility, are not directly suitable for use in pharmaceuticals but which can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts or which might be suitable for the H4 antagonist activity of a compound according of the invention in any suitable manner, such as any suitable in vitro assay.
  • the present invention furthermore includes derivatives/prodrugs (including the salts thereof) of the compounds according to the invention which contain physiologically tolerable and cleavable groups and which are metabolized in animals, preferably mammals, most preferably humans into a compound according to the invention.
  • prodrug means a derivative that is converted into a compound according to the present invention by a reaction with an enzyme, gastric acid or the like under a physiological condition in the living body, e.g. by oxidation, reduction, hydrolysis or the like, each of which is carried out enzymatically.
  • the present invention furthermore includes the metabolites of the compounds according to the invention.
  • the term relates to molecules which differ from any molecule which is present in any such cell or organism under physiological conditions.
  • Another object of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a compound according to the present invention in a mixture with an inert carrier.
  • “Pharmaceutical composition” means one or more active ingredients, and one or more inert ingredients that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by mixing a compound of the present invention and a pharmaceutically acceptable carrier.
  • Any suitable route of administration may be employed for providing a mammal, especially a human, with an effective dosage of a compound of the present invention.
  • oral, rectal, topical, parenteral, ocular, pulmonary, nasal, and the like may be employed.
  • Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like.
  • the compounds may also be delivered as powders which may be formulated and the power composition may be inhaled with the aid of insufflation powder inhaler device.
  • the preferred delivery systems for inhalation are metered dose inhalation (MDI) aerosol, which may be formulated as a suspension or solution of a compound of formula (I) in suitable propellants, such as fluorocarbons or hydrocarbons and dry powder inhalation (DPI) aerosol, which can be formulated as a dry powder of a compound of formula (I) with or without additional excipients.
  • MDI metered dose inhalation
  • suitable propellants such as fluorocarbons or hydrocarbons
  • DPI dry powder inhalation
  • Suitable topical formulations of a compound of formula (I) include transdermal devices, aerosols, creams, ointments, lotions, dusting powders and the like.
  • any of the usual pharmaceutical media may be employed, such, as, for example, water, glycols, oils, alcohols, flavouring agents, preservatives, colouring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, capsules and tablets, with the solid oral preparations being preferred over the liquid preparations. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques.
  • the compounds of formula (I) may also be administered by controlled release means and/or delivery devices such as those described in U.S patents 3845770, 3916899, 3536809, 3598123, 3630200 and 4008719.
  • a tablet may be prepared by compression or moulding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent.
  • Moulded tablets may be made by moulding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.
  • each tablet contains from about 1 mg to about 500 mg of the active ingredient and each cachet or capsule contains from about 1 to about 500 mg of the active ingredient.
  • Compound of formula (I) 25 mg / tablet Lactose Powder 573,5 mg / tablet Magnesium Stearate 1,5 mg / tablet
  • Compound of formula (I) 24 mg / canister Lecithin, NF Liq. Cone. 1 ,2 mg / canister Trichlorofluoromethane, NF 4,025 g / canister Dichlorodifluoromethane, NF 12,15 g / canister
  • Compounds of formula (I) may be used in combination with other drugs that are used in the treatment/prevention/suppression or amelioration of the diseases or conditions for which compounds of formula (I) are useful. Such other drugs may be administered, by a route and in an amount commonly used therefore, contemporaneously or sequentially with a compound of formula (I).
  • a pharmaceutical composition containing such other drugs in addition to the compound of formula (I) is preferred.
  • the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of formula (I).
  • Another object of the present invention is a compound according to the invention for use as a medicament.
  • Yet another object of the present invention is the use of a compound of the present invention for the manufacture of a medicament for the treatment or prophylaxes of one or more diseases or disorders associated with the modulation of histamine H4 receptor, especially with the inflammatory response mediated by histamine H4 receptor.
  • Yet another object of the present invention is the use of a compound according to the present invention for the manufacture of a medicament for the treatment or prophylaxes of one or more diseases or disorders selected from the group consisting of asthma, psoriasis, rheumatoid arthritis, Crohn's disease, inflammatory bowel disease, ulcerative colitis, allergic rhinitis and other allergic diseases, atopic dermatitis and other dermatological disorders.
  • diseases or disorders selected from the group consisting of asthma, psoriasis, rheumatoid arthritis, Crohn's disease, inflammatory bowel disease, ulcerative colitis, allergic rhinitis and other allergic diseases, atopic dermatitis and other dermatological disorders.
  • the present invention is also concerned with processes for preparing the compounds of this invention.
  • the compounds of formula (I) of the present invention can be prepared according to the procedures of the following schemes and examples, using appropriate materials, and are further exemplified by the following specific examples. Moreover, by utilising the procedures described with the disclosure contained herein, one of ordinary skill in the art can readily prepare additional compounds of the present invention claimed herein. The compounds illustrated in the examples are not, however, to be construed as forming the only genus that is considered as the invention. The examples further illustrate details for the preparation of the compounds of the present invention. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds.
  • Intermediate compounds of formula (V) where R 8 is chloro or bromo may be prepared, for example, by the Copper catalysed cyclisation of a compound of formula (VI) with a suitable base, for example caesium carbonate or potassium carbonate.
  • Intermediate compounds of formula (VI) may be prepared, for example, from compounds of formula (VII), by reaction with a suitable Lewis acid.
  • a suitable Lewis acid includes boron trichloride.
  • the compounds of formula (I) are claimed as having activity as pharmaceuticals, in particular as modulators of histamine H4 receptor, and may be used in the treatment (therapeutic or prophylactic) of conditions/diseases in human and non-human animals, that are known to be at least partially mediated by the activation of the H4 receptor.
  • These compounds could be beneficial for the treatment of inflammatory diseases including, but not limited to asthma, psoriasis, rheumatoid arthritis, Crohn's disease, inflammatory bowel disease, ulcerative colitis, allergic rhinitis and other allergic diseases, atopic dermatitis and other dermatological disorders.
  • Compounds of the invention of formula (I) can be tested using the following biological test methods to determine their ability to displace histamine from the H4 receptor and for their ability to antagonize the functional effects of histamine at the H4 receptor in a whole cell system.
  • the reaction is initiated with 20 ⁇ g of human histamine H4 receptor containing membranes (Euroscreen, Belgium) and the mixture incubated for 90 minutes at 25 0 C.
  • the reaction is terminated by rapid filtration through GF/B filters pre-blocked with PEI (1 % v/v) using a Packard Cell harvester and the filter washed with 2 x 500 ⁇ L / well of cold wash buffer (50 mM Tris (pH 7.4), 5 mM MgCl 2 , 0.5 M NaCl).
  • the residual radioligand bound to the filter was determined using a Topcount liquid scintillation counter (Perkin Elmer).
  • the GTP ⁇ S binding assay is used as a measure of the functional activation of the histamine H4 receptor using membranes prepared from CHO Kl cells stably transfected with the cDNA for the human histamine H4 receptor (Euroscreen, Belgium).
  • the assay is performed in a 96 well Isoplate (Perkin Elmer) in a final volume of 200 ⁇ L assay buffer (20 mM HEPES (pH 7.4), 100 mM NaCl, 10 mM MgCl 2 , 10 ⁇ g/ml saponin and 10 ⁇ M GDP) using 0.InM GTP ⁇ [35S] (Amersham Biosciences UK Ltd) to measure functional incorporation, and in the case of antagonist studies 150 nM histamine dihydrochloride (EC80 for histamine dihydrochloride) to determine maximal incorporation of GTP ⁇ [35S].
  • Method A Experiments performed on a Micromass Platform LCT spectrometer with positive ion electrospray and single wavelength UV 254nm detection using a Higgins Clipeus Cl 8 5 ⁇ m 100 x 3.0mm column and a 1 mL/minute flow rate.
  • the initial solvent system was 95% water containing 0.1% formic acid (solvent A) and 5% acetonitrile containing 0.1% formic acid (solvent B) for the first minute followed by a gradient up to 5% solvent A and 95% solvent B over the next 14 minutes. The final solvent system was held constant for a further 5 minutes.
  • Method B Experiments performed on a Micromass Platform LC spectrometer with positive and negative ion electrospray and ELS/Diode array detection using a Phenomenex Luna C 18(2) 30 x 4.6mm column and a 2 ml/minute flow rate.
  • the solvent system was 95% solvent A and 5% solvent B for the first 0.50 minutes followed by a gradient up to 5% solvent A and 95% solvent B over the next 4 minutes. The final solvent system was held constant for a further 1 minute.
  • Microwave experiments were carried out using either a Personal Chemistry Smith SynthesizerTM or Emrys OptimizerTM which use a single-mode resonator and dynamic field tuning, both of which give reproducibility and control. Temperatures from 40-250 0 C can be achieved, and pressures of up to 20bar can be reached.
  • Example 1 Preparation of [(S)-l-(2-amino-8-chlorobenzo[4,5]furo[3,2-d]pyrimidin-4- yl)pyrrolidin-3-yl] N-methyl amine (non- inventive) and [(R)-l-(2-Amino-8- chlorobenzo[4,5]furo[3,2-d]-pyrimidin-4-yl)pyrrolidin-3-yl] N-methyl amine (inventive)
  • the title compounds of example 1 were tested in the radioligand binding assay using human histamine H4 receptor transfected CHO Kl membranes as described above.
  • the R enantiomers of the invention typically demonstrate K 1 values in this assay 5-10 fold lower than the corresponding S enantiomers.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne de nouveaux énantiomères de composés d'amino pyrimidine de formule (I), destinés à moduler le récepteur H4 à l'histamine. Ces énantiomères sont destinés à traiter ou à prévenir des troubles médiés par le récepteur H4 à l'histamine. L'invention concerne également la préparation de tels composés.
PCT/EP2007/051183 2006-02-10 2007-02-07 Enantiomères de composes d'amino pyrimidine destinés à traiter des troubles inflammatoires WO2007090853A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP06101510A EP1829879A1 (fr) 2006-02-10 2006-02-10 Dérivés de amino pyrimidine pour le traitment des maladies inflammatoires
EP06101510.3 2006-02-10
EP06114490A EP1860108A1 (fr) 2006-05-24 2006-05-24 Enantiomères d'aminopyrimidines utilisés dans le traitement de maladies inflammatoires.
EP06114490.3 2006-05-24

Publications (1)

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WO2007090853A1 true WO2007090853A1 (fr) 2007-08-16

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Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2020412A1 (fr) * 2007-07-30 2009-02-04 Cellzome Limited Composés d'aminopyrimidine à base de soufre pour le traitement de trouble inflammatoires
US7576092B2 (en) 2006-07-11 2009-08-18 Janssen Pharmaceutica N.V. Benzofuro- and benzothienopyrimidine modulators of the histamine H4 receptor
WO2010072829A1 (fr) 2008-12-24 2010-07-01 INSERM (Institut National de la Santé et de la Recherche Médicale) Antagonistes sélectifs du récepteur h4 de l'histamine dans le traitement de troubles vestibulaires
WO2010084050A2 (fr) 2009-01-13 2010-07-29 Novartis Ag Dérivés de quinazolinone utiles comme antagonistes vanilloïdes
US7923451B2 (en) 2007-02-14 2011-04-12 Janssen Pharmaceutica Nv 2-aminopyrimidine modulators of the histamine H4 receptor
US7985745B2 (en) 2006-10-02 2011-07-26 Abbott Laboratories Method for pain treatment
WO2011092290A1 (fr) 2010-02-01 2011-08-04 Novartis Ag Dérivés de pyrazolo[5,1-b] utilisés en tant qu'antagonistes du récepteur de crf-1
WO2011092293A2 (fr) 2010-02-01 2011-08-04 Novartis Ag Dérivés de cyclohexylamide utilisés en tant qu'antagonistes du récepteur du crf
WO2011095450A1 (fr) 2010-02-02 2011-08-11 Novartis Ag Dérivés de cyclohexylamide à titre d'antagonistes du récepteur crf
US8193178B2 (en) 2007-09-14 2012-06-05 Janssen Pharmaceutica Nv Thieno- and furo-pyrimidine modulators of the histamine H4 receptor
WO2013182711A1 (fr) 2012-06-08 2013-12-12 Sensorion Inhibiteurs des récepteurs h4 pour le traitement des acouphènes
US8841287B2 (en) 2008-06-12 2014-09-23 Janssen Pharmaceutica N.V. Diamino-pyridine, pyrimidine, and pyrazine modulators of the histamine H4 receptor
US9905782B2 (en) 2013-03-26 2018-02-27 Semiconductor Energy Laboratory Co., Ltd. Light-emitting element, compound, organic compound, display module, lighting module, light-emitting device, display device, lighting device, and electronic device

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030207893A1 (en) * 2001-03-09 2003-11-06 Carruthers Nicholas I. Heterocyclic compounds
EP1505064A1 (fr) * 2003-08-05 2005-02-09 Bayer HealthCare AG Dérivés de 2-aminopyrimidine

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030207893A1 (en) * 2001-03-09 2003-11-06 Carruthers Nicholas I. Heterocyclic compounds
EP1505064A1 (fr) * 2003-08-05 2005-02-09 Bayer HealthCare AG Dérivés de 2-aminopyrimidine

Cited By (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8030321B2 (en) 2006-07-11 2011-10-04 Janssen Pharmaceutica, Nv Benzofuro- and benzothienopyrimidine modulators of the histamine H4 receptor
US7576092B2 (en) 2006-07-11 2009-08-18 Janssen Pharmaceutica N.V. Benzofuro- and benzothienopyrimidine modulators of the histamine H4 receptor
US7985745B2 (en) 2006-10-02 2011-07-26 Abbott Laboratories Method for pain treatment
US8716475B2 (en) 2007-02-14 2014-05-06 Janssen Pharmaceutica Nv 2-aminopyrimidine modulators of the histamine H4 receptor
US7923451B2 (en) 2007-02-14 2011-04-12 Janssen Pharmaceutica Nv 2-aminopyrimidine modulators of the histamine H4 receptor
EP2599386A1 (fr) 2007-02-14 2013-06-05 Janssen Pharmaceutica N.V. Modulateurs 2-aminopyrimidine du récepteur h4 d'histamine
US8686142B2 (en) 2007-02-14 2014-04-01 Janssen Pharmaceutica Nv 2-aminopyrimidine modulators of the histamine H4 receptor
US8415366B2 (en) 2007-02-14 2013-04-09 Janssen Pharmaceutica Nv 2-aminopyrimidine modulators of the histamine H4 receptor
EP2020412A1 (fr) * 2007-07-30 2009-02-04 Cellzome Limited Composés d'aminopyrimidine à base de soufre pour le traitement de trouble inflammatoires
US8440654B2 (en) 2007-09-14 2013-05-14 Janssen Pharmaceutica Nv Thieno- and furo-pyrimidine modulators of the histamine H4 receptor
US8193178B2 (en) 2007-09-14 2012-06-05 Janssen Pharmaceutica Nv Thieno- and furo-pyrimidine modulators of the histamine H4 receptor
US8927555B2 (en) 2007-09-14 2015-01-06 Janssen Pharmaceutica, Nv Thieno- and furo-pyrimidine modulators of the histamine H4 receptor
US8445482B2 (en) 2007-09-14 2013-05-21 Janssen Pharmaceutica Nv Thieno- and furo-pyrimidine modulators of the histamine H4 receptor
US8937075B2 (en) 2007-09-14 2015-01-20 Janssen Pharmaceutica, Nv Thieno- and furo-pyrimidine modulators of the histamine H4 receptor
US8841287B2 (en) 2008-06-12 2014-09-23 Janssen Pharmaceutica N.V. Diamino-pyridine, pyrimidine, and pyrazine modulators of the histamine H4 receptor
US9732087B2 (en) 2008-06-12 2017-08-15 Janssen Pharmaceutica N.V. Diamino-pyridine, pyrimidine, and pyridazine modulators of the histamine H4 receptor
US9526725B2 (en) 2008-12-24 2016-12-27 Inserm (Institut National De La Sante Et De La Recherche Medicale) Selective histamine H4 receptor antagonists for the treatment of vestibular disorders
US10195195B2 (en) 2008-12-24 2019-02-05 Inserm (Institut National De La Sante Et De La Recherche Medicale) Selective histamine H4 receptor antagonists for the treatment of vestibular disorders
WO2010072829A1 (fr) 2008-12-24 2010-07-01 INSERM (Institut National de la Santé et de la Recherche Médicale) Antagonistes sélectifs du récepteur h4 de l'histamine dans le traitement de troubles vestibulaires
WO2010084050A2 (fr) 2009-01-13 2010-07-29 Novartis Ag Dérivés de quinazolinone utiles comme antagonistes vanilloïdes
WO2011092290A1 (fr) 2010-02-01 2011-08-04 Novartis Ag Dérivés de pyrazolo[5,1-b] utilisés en tant qu'antagonistes du récepteur de crf-1
WO2011092293A2 (fr) 2010-02-01 2011-08-04 Novartis Ag Dérivés de cyclohexylamide utilisés en tant qu'antagonistes du récepteur du crf
WO2011095450A1 (fr) 2010-02-02 2011-08-11 Novartis Ag Dérivés de cyclohexylamide à titre d'antagonistes du récepteur crf
WO2013182711A1 (fr) 2012-06-08 2013-12-12 Sensorion Inhibiteurs des récepteurs h4 pour le traitement des acouphènes
US9688989B2 (en) 2012-06-08 2017-06-27 Sensorion H4 receptor inhibitors for treating tinnitus
EP3378476A1 (fr) 2012-06-08 2018-09-26 Sensorion Inhibiteurs du récepteur h4 destinés au traitement des acouphènes
US9905782B2 (en) 2013-03-26 2018-02-27 Semiconductor Energy Laboratory Co., Ltd. Light-emitting element, compound, organic compound, display module, lighting module, light-emitting device, display device, lighting device, and electronic device
US10193086B2 (en) 2013-03-26 2019-01-29 Semiconductor Energy Laboratory Co., Ltd. Light-emitting element, compound, Organic compound, display module, lighting module, light-emitting device, display device, lighting device, and electronic device
US10700291B2 (en) 2013-03-26 2020-06-30 Semiconductor Energy Laboratory Co., Ltd. Light-emitting element, compound, organic compound, display module, lighting module, light-emitting device, display device, lighting device, and electronic device
US11600789B2 (en) 2013-03-26 2023-03-07 Semiconductor Energy Laboratory Co., Ltd. Light-emitting element, compound, organic compound, display module, lighting module, light-emitting device, display device, lighting device, and electronic device

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