WO2007062677A1 - Acides thiazolyl et pyrimidinyl-acetiques et leurs utilisations comme ligands du recepteur crth2 - Google Patents

Acides thiazolyl et pyrimidinyl-acetiques et leurs utilisations comme ligands du recepteur crth2 Download PDF

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Publication number
WO2007062677A1
WO2007062677A1 PCT/EP2005/012870 EP2005012870W WO2007062677A1 WO 2007062677 A1 WO2007062677 A1 WO 2007062677A1 EP 2005012870 W EP2005012870 W EP 2005012870W WO 2007062677 A1 WO2007062677 A1 WO 2007062677A1
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WIPO (PCT)
Prior art keywords
disease
syndrome
phenyl
bis
methyl
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PCT/EP2005/012870
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English (en)
Inventor
Trond Ulven
Thomas Frimurer
Øystein RIST
Evi Kostenis
Thomas Högberg
Jean-Marie Receveur
Marie Grimstrup
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7Tm Pharma A/S
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Priority to PCT/EP2005/012870 priority Critical patent/WO2007062677A1/fr
Publication of WO2007062677A1 publication Critical patent/WO2007062677A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • This invention relates to the use of a class of compounds which are ligands of the CRTH2 receptor (Chemoattractant Receptor-homologous molecule expressed on T Helper cells type 2), in the treatment of diseases responsive to modulation of CRTH2 receptor activity, principally diseases having a significant inflammatory component.
  • the invention also relates to novel members of that class of ligands and pharmaceutical compositions containing them.
  • antiinflammatory agents including the non-steroidal antiinflammatory compounds known as NSAIDs and the inhibitors of cyclooxygenase (COX-1 and COX-2).
  • NSAIDs non-steroidal antiinflammatory compounds
  • COX-1 and COX-2 the inhibitors of cyclooxygenase
  • Benzoylphenylacetic acid and some benzophenone derivatives with carboxymethoxy substituents in one of the rings have been identiified as antiinfammatory agents (see, for example, Khanum et. al. Bioorganic Chemistry VoI 32, No. 4, 2004, pages 211-222 and the references cited therein).
  • Some o-phenyl carbamoyl-phenoxyacetic acids and o-benzamido-phenoxymethyl tetrazoles have been reported as potential antiinflammatory agent, see for example Drain et. al. J. Pharm.
  • WO 99/15520 discloses a few benzophenone derivatives with carboxymethoxy or tetrazolylmethoxy substituents in one of the rings, synthesised as members of a group of compounds said to have activity as inhibitors of peroxisome proliferator-activated receptor (PPAR), and utility in a variety of disease states including diabetes, cardiac disease, andcirculatory disease.
  • PPAR peroxisome proliferator-activated receptor
  • CRTH2 The natural ligand of the G-protein coupled receptor CRTH2 is prostaglandin D2.
  • CRTH2 is expressed on T helper cells type 2 (Th2 cells) but it is also known to be expressed on eosinophils and basophil cells.
  • Th2 cells T helper cells type 2
  • Cell activation as a result of binding of PGD2 to the CRTH2 receptor results in a complex biological response, including release of inflammatory mediators. Elevated levels of PGD2 are therefore associated with many diseases which have a strong inflammatory component, such as asthma, rhinitis and allergies. Blocking binding of PGD2 to the CRTH2 receptor is therefore a useful therapeutic strategy for treatment of such diseases.
  • Some small molecule ligands of CRTH2, apparently acting as antagonists of PGD2, are known, for example as proposed in the following patent publications: WO 03/097042, WO 03/097598, WO 03/066046, WO 03/066047, WO 03/101961 , WO 03/101981 , GB 2388540, WO 04/089885 and WO 05/018529.
  • Our copending international application PCT/EP2005/005882 is concerned with the use of a compound of formula (IA) or a salt, hydrate or solvate thereof in the manufacture of a composition for the treatment of disease responsive to modulation of CRTH2 receptor activity
  • A is a carboxyl group -COOH, or a carboxyl bioisostere
  • rings Ar 2 and Ar 3 each independently represent a phenyl or 5- or 6-membered monocyclic heteroaryl ring, or a bicyclic ring system consisting of a 5- or 6-membered carbocyclic or heterocyclic ring which is benz-fused or fused to a 5- or 6-membered monocyclic heteroaryl ring, said ring or ring system being optionally substituted;
  • ring B is as defined for Ar 2 and Ar 3 , or an optionally substituted N-pyrrolidinyl, N-piperidinyl or N-azepinyl ring;
  • s is O or 1 ;
  • L1 represents a divalent radical of formula -(Alk 1 ) m - and L2 and L4 each independently represents a divalent radical of formula -(Alk 1 ) m -(Z) n -(Alk 2 ) p - wherein
  • AIk 1 and AIk 2 are independently optionally substituted straight or branched chain C 1 -C 3 alkylene or C 2 -C 3 alkenylene radicals which may contain a compatible -O-, -S- or -NR- link wherein R is hydrogen or C 1 -C 3 alkyl, and
  • L3 represents a divalent radical of formula -(Alk 3 ) m -(Z) n -(Alk 2 ) p - wherein m, n, p, AIk 2 and Z are as defined in relation to L2 and L4, and Alk3 is an optionally substituted straight or branched chain C 1 -C 2 alkylene or C 1 -C 2 alkenylene radical which may contain a compatible -0-, -S- or - NR- link wherein R is hydrogen or C 1 -C 3 alkyl;
  • Qi represents hydrogen or (C r C 6 )alkyl
  • R A and R B are independently hydrogen or a (C 1 -C 6 )alkyl group, or R A and R B are linked to the same N atom to form a cyclic amino ring, or
  • This invention relates to certain compounds falling withinthe general ambit of, but not specifically disclosed in PCT/EP2005/005882, and which have the CRTH2 receptor activity and utilities described in that application.
  • Pharmaceutical compositions comprising a compound selected from the foregoing group together with a pharmaceutically acceptable carrier, also form part of the invention.
  • the invention provides the use of a compound selected from the foregoing group in medicine, particularly in the manufacture of a medicament for treatment diseases responsive to modulation of CRTH2 receptor activity,
  • the invention provides a method of treatment of a subject suffering from a disease responsive to modulation of CRTH2 receptor activity, which comprised administering to the subject an amount of a compound selected from the foregoing group effective to ameliorate the disease.
  • compounds with which the invention is concerned are useful in the treatment of disease associated with elevated levels of prostaglandin D2 (PGD2) or one or more active metabolites thereof.
  • PGD2 prostaglandin D2
  • diseases include asthma, rhinitis, allergic airway syndrome, allergic rhinobronchitis, bronchitis, chronic obstructive pulmonary disease (COPD), nasal polyposis, sarcoidosis, farmer ' s lung, fibroid lung, cystic fibrosis, chronic cough, conjunctivitis, atopic dermatitis, Alzheimer's disease, amyotrophic lateral sclerosis, AIDS dementia complex, Huntington's disease, frontotemporal dementia, Lewy body dementia, vascular dementia, Guillain-Barre syndrome, chronic demyelinating polyradiculoneurophathy, multifocal motor neuropathy, plexopathy, multiple sclerosis, encephalomyelitis, panencephalitis, cerebellar degeneration and encephalomyelitis, CNS trauma, migraine, stroke, rheumatoid arthritis, ankylosing spondylitis, Beh ⁇ et's Disease, bursitis, carpal tunnel syndrome, inflammatory s
  • the compounds with which the invention is concerned are primarily of value for the treatment of asthma, rhinitis, allergic airway syndrome, and allergic rhinobronchitis.
  • treatment includes prophylactic treatment.
  • salt includes base addition, acid addition and quaternary salts.
  • Compounds of the invention which are acidic can form salts, including pharmaceutically acceptable salts, with bases such as ammonium hydroxide; alkali metal hydroxides, e.g. sodium and potassium hydroxides; alkaline earth metal hydroxides e.g. calcium, barium and magnesium hydroxides; with organic bases e.g. N-methyl-D-glucamine, choline tris(hydroxymethyl)amino-methane, L-arginine, L-lysine, N-ethyl piperidine, dibenzylamine and the like.
  • bases such as ammonium hydroxide; alkali metal hydroxides, e.g. sodium and potassium hydroxides; alkaline earth metal hydroxides e.g. calcium, barium and magnesium hydroxides; with organic bases e.g. N-methyl-D-glucamine, choline tris(hydroxymethyl)amino-methane, L-arginine
  • Those compounds (I) which are basic can form salts, including pharmaceutically acceptable salts with inorganic acids, e.g. with hydrohalic acids such as hydrochloric or hydrobromic acids, sulphuric acid, nitric acid or phosphoric acid and the like, and with organic acids e.g. with acetic, tartaric, succinic, fumaric, maleic, malic, salicylic, citric, methanesulphonic, p-toluenesulphonic, benzoic, benzenesunfonic, glutamic, lactic, and mandelic acids and the like.
  • hydrohalic acids such as hydrochloric or hydrobromic acids, sulphuric acid, nitric acid or phosphoric acid and the like
  • organic acids e.g. with acetic, tartaric, succinic, fumaric, maleic, malic, salicylic, citric, methanesulphonic, p-toluenesulphonic, benzo
  • the compounds with which the invention is concerned are capable of modulating CRTH2 activity, and are useful in the treatment of diseases which benefit from such modulation.
  • diseases include asthma, allergy and rhinitis.
  • the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing treatment. Optimum dose levels and frequency of dosing will be determined by clinical trial, as is required in the pharmaceutical art.
  • the compounds with which the invention is concerned may be prepared for administration by any route consistent with their pharmacokinetic properties.
  • the orally administrable compositions may be in the form of tablets, capsules, powders, granules, lozenges, liquid or gel preparations, such as oral, topical, or sterile parenteral solutions or suspensions.
  • Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricant, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants for example potato starch, or acceptable wetting agents such as sodium lauryl sulphate.
  • the tablets may be coated according to methods well known in normal pharmaceutical practice.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, glucose syrup, gelatin hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.
  • suspending agents for example sorbitol, syrup, methyl cellulose, glucose syrup, gelatin hydrogenated edible fats
  • emulsifying agents for example lecithin, sorbitan monooleate, or acacia
  • non-aqueous vehicles which may include edible oils
  • almond oil fractionated coconut oil
  • oily esters such as glycerine, propylene
  • the drug may be made up into a cream, lotion or ointment.
  • Cream or ointment formulations which may be used for the drug are conventional formulations well known in the art, for example as described in standard textbooks of pharmaceutics such as the British Pharmacopoeia.
  • the drug may be made up into a solution or suspension in a suitable sterile aqueous or non aqueous vehicle.
  • Additives for instance buffers such as sodium metabisulphite or disodium edeate; preservatives including bactericidal and fungicidal agents such as phenyl mercuric acetate or nitrate, benzalkonium chloride or chlorhexidine, and thickening agents such as hypromellose may also be included.
  • the drug may also be formulated for inhalation, for example as a nasal spray, or dry powder or aerosol inhalers.
  • the active ingredient may also be administered parenterally in a sterile medium.
  • the drug can either be suspended or dissolved in the vehicle.
  • adjuvants such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle.
  • the compounds with which the invention is concerned may be administered alone, or as part of a combination therapy with other drugs used for treatment of diseases with a major inflammatory component.
  • drugs used for treatment of diseases with a major inflammatory component.
  • such drugs include corticosteroids, long-acting inhaled beta agonists, cromolyn, nedocromil, theophylline, leukotriene receptor antagonists, antihistamines, and anticholinergics (e.g. ipratropium), and are often administered as nasal sprays, dry powder or aerosol inhalers.
  • glucocorticoids Non Steroidal Anti-Inflammatory Drugs - conventional prostaglandin synthesis inhibitors, COX-2 inhibitors, salicylates
  • DMARDs disease-modifying antirheumatic drugs such as methotrexate, sulfasalazine, gold, cyclosporine.
  • Microwave chemistry was performed in a Personal Chemistry Emrys Optimizer. NMR spectra were obtained on a Bruker Avance AMX 300 MHz instrument. LC/MS was performed on an
  • Analytical an20p5 Column: Gemini 5 ⁇ C18 2.0x50 mm; Flow: 1.2 mL/min; Gradient: 0-3.5 min: 10-95% MeCN in water, 3.5-4.5 min: 95% , MeCN; Modifier: 5 mM ammonium formate;
  • Analytical an20n5 Column: Gemini 5 ⁇ C18 2.0x50 mm; Flow: 1.2 mL/min; Gradient: 0-3.5 min: 10-95% MeCN in water, 3.5-4.5 min: 95% MeCN; Modifier: 5 mM ammonium formate;
  • MS-ionisation mode API-ES (neg.)
  • Analytical tfa20p5 Column: Gemini 5 ⁇ C18 2.0x50 mm; Flow: 1.2 mL/min; Gradient: 0-3.5 min: 10-95% MeCN in water, 3.5-4.5 min: 95% MeCN; Modifier: 0.1% TFA;
  • MS-ionisation mode API-ES (pos.)
  • Step 1.1 Step 1.2
  • Step 1.3 Step 1.4
  • Example 1 Compound A1 (prepared by Step 1.4) [2-[Bis-(4-fluoro-phenyl)methyl]-4-(2-methylpyridin-4-yl)thiazol-5-yl]acetic acid.
  • Suzuki coupling lntermediate-3 (0.38 g, 0.77 mmol), 2-picoline-4-boronic acid (0.21 g, 1.5 mmol) and sat. Na 2 CO 3 solution (1.2 ml.) was suspended in dry dioxane (3 ml_). The reaction mixture was flushed with N 2 for 15 min. PdCI 2 (dppf) (10 mg, 0.038 mmol) was added under under N 2 . The reaction mixture was stirred at 80 0 C over night. 1 N HCI was added and then the mixture was extracted with DCM. The organic phase was passed through a phase separation filter and concentrated.
  • Example 2 Compound A2 (prepared by Step 2.1) ⁇ 4-(2-Aminopyridin-4-yl)-2-[bis-(4-fluorophenyl)methyl]thiazol-5-yl ⁇ acetic acid.
  • Example 3 Compound A3 (prepared by Step 3.4) [2-[Bis-(4-fluoro-phenyl)-methyl]-4-(3-fluoro-phenyl)-pyrimidin-5-yl]acetic acid.
  • Table 1 gives the biological test results for the compounds synthesised above
  • the coding sequence of the human CRTH2 receptor (genbank accession no NM_004778) was amplified by PCR from a human hippocampus cDNA library and inserted into the pcDNA3.1(+) expression vector (invitrogen) via 5' Hind/// and 3' EcoR/.
  • CRTH2-Renilla luciferase (CRTH2-Rluc) fusion protein
  • the CRTH2 coding sequence without a STOP codon and Rluc were amplified, fused in frame by PCR and subcloned into the pcDNA3.1(+)Zeo expression vector (invitrogen).
  • ⁇ -arrestin2 ( ⁇ -arr2) N-terminally tagged with GFP 2 ( ⁇ arr2-GFP 2 ) and Renilla luciferase were purchased from BioSignal Packard Inc, (Montreal, Canada). The sequence identity of the construct was verified by restriction endonuclease digests and sequencing in both directions on an ABI Prism (Applied Biosystems, Foster City, CA).
  • COS-7 cells were grown in Dulbecco's modified Eagle's medium (DMEM) 1885 supplemented with 10% fetal bovine serum, 100 units/ml penicillin, 1000 ⁇ g/ml streptomycin, and kept at 37 0 C in a 10% CO 2 atmosphere.
  • DMEM Dulbecco's modified Eagle's medium
  • HEK293 cells were maintained in Minimum Essential medium (MEM) supplemented with 10% (v/v) heat inactivated fetal calf serum (HIFCS), 2mM GlutamaxTM-!, 1 % non essential amino acids (NEAA), 1% sodium pyruvate and 10 ⁇ g/ml gentamicin.
  • MEM Minimum Essential medium
  • HFCS Heat inactivated fetal calf serum
  • NEAA non essential amino acids
  • sodium pyruvate 10 ⁇ g/ml gentamicin.
  • COS7 cells were transiently transfected with the CRTH2 receptor using a calcium phosphate-DNA coprecipitation method with the addition of chloroquine (as described by Hoist et al., 2001*).
  • BRET Bioluminescence Resonance Energy Transfer
  • Binding assay 24h after transfection COS-7 cells were seeded into 96well plates at a density of 30.000 cells/well. Competition binding experiments on whole cells were then performed about 18-24 h later using 0.1 nM [ 3 H]PGD2 (NEN, 172 Ci/mmol) in a binding buffer consisting of HBSS (GIBCO) and 10 mM HEPES. Competing ligands were diluted in DMSO which was kept constant at 1% (v/v) of the final incubation volume. Total and nonspecific binding were determined in the absence and presence of 10 ⁇ M PGD2. Binding reactions were routinely conducted for 3 h at 4°C and terminated by 2 washes (100 ⁇ l each) with ice cold binding buffer.
  • Radioactivity was determined by liquid scintillation counting in a TOPCOUNTER (Packard) following over night incubation in Microscint 20.
  • Stable HEK293 cells were seeded at a density of 30.000 cells/well 18-24 h prior to the binding assay which was performed essentially as described for COS7 cells above. Determinations were made in duplicates.
  • BRET assay Functional BRET assays were performed on HEK293 cells stably expressing human CRTH2-Rluc and GFP 2 - ⁇ -arr2. Prior to their use in the BRET assay cells were detached and re-suspended in D-PBS with 1000 mg/L L-Glucose at a density of 2x10 6 cells/mL DeepBlueCTM was diluted to 50 ⁇ M in D-PBS with 1000 mg/L L-Glucose (light sensitive). 100 ⁇ l_ of cell suspension was transferred to wells in a 96-well microplate (white OptiPlate) and placed in the Mithras LB 940 instrument (BERTHOLD TECHNOLOGIES, Bad Wildbad, Germany).

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  • Pulmonology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
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  • Pharmacology & Pharmacy (AREA)
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  • General Health & Medical Sciences (AREA)
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  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Acide [2-[Bis-(4-fluoro-phényl)méthyl]-4-(2-méthylpyridin-4-yl)thiazol-5-yl]acétique, acide {4-(2-aminopyridin-4-yl)-2-[bis-(4-fluorophényl)méthyl]thiazol-5-yl}acétique, acide [2-[bis-(4-fluoro-phényl)-méthyl]-4-(3-fluoro-phényl)-pyrimidin-5-yl]acétique, y compris leurs sels, hydrates et solvates, à la fois comme ligands du récepteur CRTH2, et comme produits utiles pour le traitement, entre autres, de l'asthme, de la rhinite, du syndrome allergique des voies respiratoires, ou de la rhino-bronchite allergique.
PCT/EP2005/012870 2005-11-30 2005-11-30 Acides thiazolyl et pyrimidinyl-acetiques et leurs utilisations comme ligands du recepteur crth2 WO2007062677A1 (fr)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2010540520A (ja) * 2007-09-25 2010-12-24 アクチミス ファーマシューティカルズ インコーポレーテッド Ｃｒｔｈ２アンタゴニストとしてのアルキルチオピリミジン
WO2011015641A1 (fr) * 2009-08-05 2011-02-10 Katholieke Universiteit Leuven Nouveaux inhibiteurs de réplication virale
EP2457900A1 (fr) 2010-11-25 2012-05-30 Almirall, S.A. Nouveaux dérivés de pyrazole présentant un comportement antagoniste CRTH2
WO2013088109A1 (fr) 2011-12-16 2013-06-20 Oxagen Limited Combinaison d'un antagoniste de crth2 et d'un inhibiteur de pompe à protons pour le traitement de l'œsophagite à éosinophiles
US8785638B2 (en) 2009-05-15 2014-07-22 Katholieke Universiteit Leuven Thieno [2, 3-B] pyridine derivatives as viral replication inhibitors
US9132129B2 (en) 2010-11-15 2015-09-15 Katholieke Universiteit Leuven Antiviral compounds

Citations (1)

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Publication number Priority date Publication date Assignee Title
WO2004096777A1 (fr) * 2003-04-25 2004-11-11 Actimis Pharmaceuticals, Inc. Derives de pyrimidine utiles pour le traitement des maladies mediees par crth2

Patent Citations (1)

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Publication number Priority date Publication date Assignee Title
WO2004096777A1 (fr) * 2003-04-25 2004-11-11 Actimis Pharmaceuticals, Inc. Derives de pyrimidine utiles pour le traitement des maladies mediees par crth2

Non-Patent Citations (1)

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Title
NAGATOMI H ET AL: "Studies on the anti-inflammatory activity and ulcerogenic adverse effects of thiazole derivatives, especially 2-amino-thiazoleacetic acid derivatives", ARZNEIMITTEL FORSCHUNG. DRUG RESEARCH, vol. 34(I), no. 5, 1984, pages 599 - 603, XP001074027 *

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2010540520A (ja) * 2007-09-25 2010-12-24 アクチミス ファーマシューティカルズ インコーポレーテッド Ｃｒｔｈ２アンタゴニストとしてのアルキルチオピリミジン
US8785638B2 (en) 2009-05-15 2014-07-22 Katholieke Universiteit Leuven Thieno [2, 3-B] pyridine derivatives as viral replication inhibitors
US9499563B2 (en) 2009-05-15 2016-11-22 Katholieke Universiteit Leuven Thieno [2, 3-B] pyridine derivatives as viral replication inhibitors
WO2011015641A1 (fr) * 2009-08-05 2011-02-10 Katholieke Universiteit Leuven Nouveaux inhibiteurs de réplication virale
JP2013501034A (ja) * 2009-08-05 2013-01-10 カトリック・ユニベルシティト・ルーヴァン 新規ウイルス複製阻害剤
AU2010280695B2 (en) * 2009-08-05 2014-09-11 Katholieke Universiteit Leuven Novel viral replication inhibitors
US8906906B2 (en) 2009-08-05 2014-12-09 Katholieke Universiteit Leuven Viral replication inhibitors
US20150051195A1 (en) * 2009-08-05 2015-02-19 Katholieke Universiteit Leuven Novel viral replication inhibitors
US9132129B2 (en) 2010-11-15 2015-09-15 Katholieke Universiteit Leuven Antiviral compounds
EP2457900A1 (fr) 2010-11-25 2012-05-30 Almirall, S.A. Nouveaux dérivés de pyrazole présentant un comportement antagoniste CRTH2
WO2012069175A1 (fr) 2010-11-25 2012-05-31 Almirall, S.A. Nouveaux dérivés de pyrazole possédant un comportement antagoniste de crth2
WO2013088109A1 (fr) 2011-12-16 2013-06-20 Oxagen Limited Combinaison d'un antagoniste de crth2 et d'un inhibiteur de pompe à protons pour le traitement de l'œsophagite à éosinophiles

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