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WO2002047669A1 - Utilisation d'agonistes du recepteur ep4 pour le traitement de douleurs neuropathiques - Google Patents

Utilisation d'agonistes du recepteur ep4 pour le traitement de douleurs neuropathiques Download PDF

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Publication number
WO2002047669A1
WO2002047669A1 PCT/GB2001/005501 GB0105501W WO0247669A1 WO 2002047669 A1 WO2002047669 A1 WO 2002047669A1 GB 0105501 W GB0105501 W GB 0105501W WO 0247669 A1 WO0247669 A1 WO 0247669A1
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WIPO (PCT)
Prior art keywords
pharmaceutically acceptable
acceptable derivatives
receptor
neuropathic pain
receptor agonist
Prior art date
Application number
PCT/GB2001/005501
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English (en)
Inventor
Steven Michael Foord
Gerard Martin Paul Giblin
Richard John Wilson
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Glaxo Group Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Glaxo Group Limited filed Critical Glaxo Group Limited
Priority to AU2002222191A priority Critical patent/AU2002222191A1/en
Publication of WO2002047669A1 publication Critical patent/WO2002047669A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • A61K31/5575—Eicosanoids, e.g. leukotrienes or prostaglandins having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • A61K31/5578—Eicosanoids, e.g. leukotrienes or prostaglandins having a pentalene ring system, e.g. carbacyclin, iloprost
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • 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]
    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect

Definitions

  • the present invention relates to new uses for EP4 receptor agonists in the treatment of neuropathic pain.
  • the EP4 receptor is a 7-transmembrane receptor and its natural ligand is the prostaglandin PGE 2 .
  • PGE 2 also has affinity for the other EP receptors (types EP1, EP2 and EP3).
  • the EP4 receptor is associated with smooth muscle relaxation, inflammatory activities, lymphocyte differentiation, allergic activities, renal regulation and gastric or enteric mucous secretion.
  • EP4 receptor agonists exhibit a number of advantages over current non-steroidal anti-inflammatory (NSAID) and cyclo- oxygenase-2 inhibitor (COX-2i) drugs which act via a number of prostaglandin pathways.
  • NSAID non-steroidal anti-inflammatory
  • COX-2i cyclo- oxygenase-2 inhibitor
  • EP4 receptor ligands and antagonists including [4-(4,9-diethoxy-1- oxo-1 ,3-dihydro-2H-benzo[f]isoindol-2-yl)phenyl]acetic acid and pharmaceutically acceptable derivatives thereof, in the treatment of neuropathic pain has been disclosed in PCT/EP/00/07669 (Glaxo Group Limited), unpublished at the priority date of the instant application.
  • EP4 receptor agonists are of use in the treatment of neuropathic pain.
  • Neuropathic pain syndromes can develop following neuronal injury and the resulting pain may persist for months or years, even after the original injury has healed. Neuronal injury may occur in the peripheral nerves, dorsal roots, spinal cord or certain regions in the brain. Neuropathic pain syndromes are traditionally classified according to the disease or event that precipitated them. Neuropathic pain syndromes include: diabetic neuropathy; sciatica; non-specific lower back pain; multiple sclerosis pain; fibromyalgia; HIV-related neuropathy; post-herpetic neuralgia; trigeminal neuralgia; and pain resulting from physical trauma, amputation, cancer, toxins or chronic inflammatory conditions. These conditions are difficult to treat and although several drugs are known to have limited efficacy, complete pain control is rarely achieved.
  • neuropathic pain The symptoms of neuropathic pain are heterogeneous and are often described as spontaneous shooting and lancinating pain, or ongoing, burning pain.
  • pain associated with normally non-painful sensations such as "pins and needles" (paraesthesias and dysesthesias), increased sensitivity to touch (hyperesthesia), painful sensation following innocuous stimulation (dynamic, static or thermal allodynia), increased sensitivity to noxious stimuli (thermal, cold, mechanical hyperalgesia), continuing pain sensation after removal of the stimulation (hyperpathia) or an absence of or deficit in selective sensory pathways (hypoalgesia).
  • the present invention provides the novel use of an EP4 receptor agonist and pharmaceutically acceptable derivatives thereof for the manufacture of a medicament for the treatment of neuropathic pain.
  • the present invention provides the novel use of an EP4 receptor agonist and pharmaceutically acceptable derivatives thereof for the manufacture of a medicament for the treatment of neuropathic pain, excluding the use of [4-(4,9-diethoxy-1-oxo-1 ,3-dihydro-2H-benzo[f]isoindol-2 ⁇ yl)phenyl]acetic acid and pharmaceutically acceptable derivatives thereof.
  • pharmaceutically acceptable derivative any pharmaceutically acceptable salt or solvate of an EP4 receptor agonist, or any other compound which upon administration to the recipient is capable of providing (directly or indirectly) an EP4 receptor agonist or an active metabolite or residue thereof.
  • the invention provides a novel method of treating neuropathic pain in a mammal, including man, comprising administration of an effective amount of an EP4 receptor agonist or a pharmaceutically acceptable derivative thereof. It is to be understood that reference to treatment as used herein includes treatment of established symptoms and prophylactic treatment, unless explicitly stated otherwise.
  • the ability of the compounds to agonise EP4 receptors may be demonstrated in the [ 125 l]cAMP Scintillation Proximity Assay (hereafter referred to as 'the cAMP assay').
  • the cAMP assay utilises HEK-293 cells expressing the recombinant human EP4 receptor, obtainable from Receptor Biology, Inc. Beltsville, MD, USA. The cells are cultured in Dulbecco's Modified Eagle Medium - HAM F12 mix (DMEM-F12), containing 10% heat inactivated-foetal bovine serum (FBS) and 2mM L-glutamine. The cells are either passaged into fresh medium or used in an assay once 90% confluency as determined visually had been achieved.
  • DMEM-F12 Dulbecco's Modified Eagle Medium - HAM F12 mix
  • FBS heat inactivated-foetal bovine serum
  • the cells are harvested by treatment with Versene, re-suspended in fresh culture medium and plated out to yield approximately 10,000 cells per well of a 96-well plate for overnight culture in culture medium additionally supplemented with 3 ⁇ M indomethacin.
  • the culture medium is replaced with assay medium (DMEM-F12 containing 300 ⁇ M isobutylmethylxanthine (IBMX) and 3 ⁇ M indomethacin) and incubated for 30 minutes.
  • the cells are challenged with varying concentrations of test compounds or known control agonists for 15 minutes in order to construct agonist concentration-effect curves.
  • the reaction is stopped by the aspiration of the assay medium and the addition of ice-cold ethanol.
  • EP4 receptor ligands including EP4 receptor agonists, have been' described in WO00/03980, WO00/15608, WO00/21542, WO99/02164, WO01/37877 and Bioorganic and Medicinal Chemistry Letters (2001), 11(15) pages 2029-2031 and 2033-2035, all incorporated herein by reference. These applications and publications also describe suitable methods for the preparation of EP4 receptor ligands and doses for their administration.
  • prostaglandin E ⁇ prostaglandin E 2
  • misoprostal 19-hydroxy prostaglandin E 2
  • 9-oxo-8-phenyl-8-(5- phenylpentyl)decanoic acid 8-acetyl-8-phenyl-13-phenoxytridecanoic acid and the pharmaceutically acceptable salts thereof, and mixtures thereof.
  • R is hydrogen, a salt moiety (e.g. alkali or ammonium), a straight or branched, saturated or unsaturated alkyl cahin, preferably with 1-10 carbon atoms, an alicyclic ring, preferably with 3-8 carbons, arylalkyl, preferably-C2-5 alkyly, or an aryl ring;
  • a salt moiety e.g. alkali or ammonium
  • alkyl cahin preferably with 1-10 carbon atoms, an alicyclic ring, preferably with 3-8 carbons, arylalkyl, preferably-C2-5 alkyly, or an aryl ring
  • X is a straight saturated or unsaturated alkyl chain, preferably containing 2-5 carbon atoms, optionally interrupted by a heteroatom, selected from oxygen, nitrogen and sulfur, and optionally containing a cycloalkyl, aryl, or a heteroaryl group;
  • R1 and R2 which are identical or different, are hydrogen, hydroxy, halogen, oxygen (keto or alkoxy) or an alkyl group with 1-3 carbons or an ester OCOR3, where R3 is a straight or branched, saturated or unsaturated alkyl group, preferably containing 1-10 , especially 1-6 carbons, or a cycloalkyl, preferably containing 3-7 carbons, or an arylalkyl group, especially aryl C2-5 alkyl (e.g. benzyl);
  • Z is an alkyl chain of 1-8 carbons, saturated or unsaturated, optionally interrupted by one or more heteroatoms (O, N, S), straight or branched containing alkyl substituents, or containing an alicyclic ring or an aryl or heteroaryl ring, and containing one or more, preferably one substituent Y, selected form hydroxy, oxygen (keto), hydroxy, sulfhydryl, amino, methylamino, dimethylamino and C ⁇ . 3 alkoxy.
  • the precise amount of the compounds administered to a host, particularly a human patient, will be the responsibility of the attendant physician. However, the dose employed will depend upon a number of factors including the age and sex of the patient, the precise condition being treated and its severity, and the route of administration.
  • the compounds for use in the invention may be administered orally at a dose of from 0.005 to 10 mg/kg body weight per day, such as from 0.01 to 5 mg/kg body weight per day, more particularly from 0.1 to 3 mg/kg body weight per day, calculated as the free base, which may be administered in single or divided doses, for example one to four doses.
  • compositions are conveniently administered in the form of pharmaceutical compositions.
  • Such compositions may conveniently be presented for use in conventional manner in admixture with one or more physiologically acceptable carriers or excipients.
  • a pharmaceutical composition comprising an EP4 receptor agonist or a pharmaceutically acceptable derivative thereof for use in the treatment of neuropathic pain.
  • the compounds While it is possible for the compounds to be administered as the raw chemical, it is preferable to present it as a pharmaceutical formulation.
  • the formulations comprise the compounds together with one or more acceptable carriers or diluents therefor and optionally other therapeutic ingredients.
  • the carrier(s) must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • the formulations include those suitable for oral, parenteral (including subcutaneous e.g. by injection or by depot tablet, intradermal, intrathecal, intramuscular e.g. by depot and intravenous), rectal and topical (including dermal, buccal and sublingual) administration although the most suitable route may depend upon for example the condition and disorder of the recipient.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association the compounds ("active ingredient") with the carrier which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
  • Formulations suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets (e.g. chewable tablets in particular for paediatric administration) each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in- oil liquid emulsion.
  • the active ingredient may also be presented as a bolus, electuary or paste.
  • a tablet may be made 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 a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, 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.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein.
  • Formulations for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of a sterile liquid carrier, for example, water-for-injection, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
  • Formulations for rectal administration may be presented as a suppository with the usual carriers such as cocoa butter, hard fat or polyethylene glycol.
  • Formulations for topical administration in the mouth include lozenges comprising the active ingredient in a flavoured basis such as sucrose and acacia or tragacanth, and pastilles comprising the active ingredient in a basis such as gelatin and glycerin or sucrose and acacia.
  • the compounds may also be formulated as depot preparations. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • formulations may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavouring agents.
  • EP4 receptor agonist compounds for use in the instant invention may be used in combination with other therapeutic agents, for example COX-2 inhibitors, such as celecoxib, rofecoxib, valdecoxib or parecoxib; 5-lipoxygenase inhibitors;
  • NSAID's such as diclofenac, indomethacin, nabumetone or ibuprofen; leukotriene receptor antagonists; DMARD's such as methotrexate; adenosine A1 receptor agonists; sodium channel blockers, such as lamotrigine; NMDA receptor modulators, such as glycine receptor antagonists; gabapentin and related compounds; tricyclic antidepressants such as amitriptyline; neurone stabilising antiepileptic drugs; mono-aminergic uptake inhibitors such as venlafaxine; opioid analgesics; local anaesthetics; and 5HT ⁇ agonists, such as triptans, for example sumatriptan, naratriptan, zolmitriptan, eletriptan, frovatriptan, almotriptan or rizatriptan.
  • triptans for example sumatriptan, naratriptan, zolmitriptan,
  • the compounds When the compounds are used in combination with other therapeutic agents, the compounds may be administered either sequentially or simultaneously by any convenient route.
  • the invention thus provides, in a further aspect, the use of a combination comprising an EP4 receptor agonist with one or more further therapeutic agents in the treatment of neuropathic pain.
  • compositions comprising a combination as defined above together with a pharmaceutically acceptable carrier or excipient comprise a further aspect of the invention.
  • the individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations.
  • each compound may differ from that when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art.
  • CCI chronic constriction injury
  • [4-(4,9-Diethoxy-1-oxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl)phenyl]acetic acid (10mgkg -1 b.i.d. PO) was dosed chronically for 14 days (days 20-33 post- operative). A reversal of the CCI-induced decrease in paw withdrawal threshold became apparent following 3 days of chronic dosing which was maximal after 1 week. This reversal was maintained throughout the remainder of the dosing period. Following cessation of the drug treatment the paw withdrawal threshold returned to that of the vehicle treated CCI-operated animals.

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

Abstract

La présente invention concerne l'utilisation d'un agoniste du récepteur EP4 et de dérivés pharmaceutiquement acceptables permettant la fabrication d'un médicament destiné à traiter la douleur neuropathique, à l'exception de l'utilisation d'acide [4-(4,9-diéthoxy-1-oxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl)phényl] acétique et de dérivés pharmaceutiquement acceptables.
PCT/GB2001/005501 2000-12-14 2001-12-13 Utilisation d'agonistes du recepteur ep4 pour le traitement de douleurs neuropathiques WO2002047669A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2002222191A AU2002222191A1 (en) 2000-12-14 2001-12-13 Use of ep4 receptor agonists for treating neuropathic pain

Applications Claiming Priority (2)

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GB0030541.7 2000-12-14
GBGB0030541.7A GB0030541D0 (en) 2000-12-14 2000-12-14 Medical uses

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005102389A3 (fr) * 2004-04-20 2006-08-17 Pfizer Prod Inc Combinaisons contenant des ligands de alpha-2-delta
WO2007088189A1 (fr) * 2006-02-03 2007-08-09 Glaxo Group Limited Dérivés de benzoisoindole utilisés dans le traitement de la douleur
WO2007088190A1 (fr) 2006-02-03 2007-08-09 Glaxo Group Limited Dérivés de l'acide benzo(f)isoindol-2-ylphényl acétique comme agonistes du récepteur ep4
WO2009056582A1 (fr) 2007-11-02 2009-05-07 Glaxo Group Limited Nouveaux composés
EP2465537A1 (fr) 2002-10-10 2012-06-20 ONO Pharmaceutical Co., Ltd. Promoteurs de production de facteur de réparation endogène
WO2014069401A1 (fr) 2012-10-29 2014-05-08 株式会社カルディオ Agent thérapeutique spécifique de maladie pulmonaire
US9968716B2 (en) 2013-10-15 2018-05-15 Ono Pharmaceutical Co., Ltd. Drug-eluting stent graft

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JPH08277222A (ja) * 1995-04-05 1996-10-22 Green Cross Corp:The 神経疾患の予防治療剤
WO2000003980A1 (fr) * 1998-07-15 2000-01-27 Ono Pharmaceutical Co., Ltd. DERIVES DE PHENYL-POSTAGLANDINE E 5-THIA-φ-SUBSTITUES, PROCEDE DE PRODUCTION DESDITS DERIVES ET MEDICAMENTS CONTENANT LESDITS DERIVES EN TANT QUE PRINCIPE ACTIF
WO2000015608A1 (fr) * 1998-09-14 2000-03-23 Ono Pharmaceutical Co., Ltd. Derives e de phenyl-prostaglandine a substitution-φ et medicaments les contenant comme ingredient actif
WO2000021542A1 (fr) * 1998-10-15 2000-04-20 Merck & Co., Inc. Methodes de stimulation de la formation osseuse
WO2001010426A2 (fr) * 1999-08-10 2001-02-15 Glaxo Group Limited Utilisation de ligands du recepteur ep4 dans le traitement de la douleur neuropathique et du cancer du colon, entre autres

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WO2000003980A1 (fr) * 1998-07-15 2000-01-27 Ono Pharmaceutical Co., Ltd. DERIVES DE PHENYL-POSTAGLANDINE E 5-THIA-φ-SUBSTITUES, PROCEDE DE PRODUCTION DESDITS DERIVES ET MEDICAMENTS CONTENANT LESDITS DERIVES EN TANT QUE PRINCIPE ACTIF
WO2000015608A1 (fr) * 1998-09-14 2000-03-23 Ono Pharmaceutical Co., Ltd. Derives e de phenyl-prostaglandine a substitution-φ et medicaments les contenant comme ingredient actif
EP1114816A1 (fr) * 1998-09-14 2001-07-11 Ono Pharmaceutical Co., Ltd. DERIVES E DE PHENYL-PROSTAGLANDINE A SUBSTITUTION-$g(V) ET MEDICAMENTS LES CONTENANT COMME INGREDIENT ACTIF
WO2000021542A1 (fr) * 1998-10-15 2000-04-20 Merck & Co., Inc. Methodes de stimulation de la formation osseuse
WO2001010426A2 (fr) * 1999-08-10 2001-02-15 Glaxo Group Limited Utilisation de ligands du recepteur ep4 dans le traitement de la douleur neuropathique et du cancer du colon, entre autres

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YAMAMOTO T., ET AL: "OP-1206, a prostaglandin E1 derivative, attenuates the thermal hyperesthesia induced by constriction injury to the sciatic nerve in the rat.", ANESTH. ANALG., vol. 80, no. 3, 1995, pages 515 - 520, XP001064130 *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2465537A1 (fr) 2002-10-10 2012-06-20 ONO Pharmaceutical Co., Ltd. Promoteurs de production de facteur de réparation endogène
WO2005102389A3 (fr) * 2004-04-20 2006-08-17 Pfizer Prod Inc Combinaisons contenant des ligands de alpha-2-delta
WO2007088189A1 (fr) * 2006-02-03 2007-08-09 Glaxo Group Limited Dérivés de benzoisoindole utilisés dans le traitement de la douleur
WO2007088190A1 (fr) 2006-02-03 2007-08-09 Glaxo Group Limited Dérivés de l'acide benzo(f)isoindol-2-ylphényl acétique comme agonistes du récepteur ep4
EA014428B1 (ru) * 2006-02-03 2010-12-30 Глэксо Груп Лимитед Производные бензоизоиндола для лечения боли
EP2457897A1 (fr) 2006-02-03 2012-05-30 Glaxo Group Limited Dérivés de l'acide benzo(f)isoindol-2-ylphényl acétique comme agonistes du récepteur ep4
US8207213B2 (en) 2006-02-03 2012-06-26 Glaxo Group Limited Benzoisoindole derivatives for the treatment of pain
WO2009056582A1 (fr) 2007-11-02 2009-05-07 Glaxo Group Limited Nouveaux composés
WO2014069401A1 (fr) 2012-10-29 2014-05-08 株式会社カルディオ Agent thérapeutique spécifique de maladie pulmonaire
US9968716B2 (en) 2013-10-15 2018-05-15 Ono Pharmaceutical Co., Ltd. Drug-eluting stent graft

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GB0030541D0 (en) 2001-01-31

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