WO1998050075A1 - Inhibiteurs de cox-2 en combinaison avec des agents bloquants le nmda pour traiter la douleur - Google Patents

Inhibiteurs de cox-2 en combinaison avec des agents bloquants le nmda pour traiter la douleur Download PDF

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Publication number
WO1998050075A1
WO1998050075A1 PCT/US1998/009252 US9809252W WO9850075A1 WO 1998050075 A1 WO1998050075 A1 WO 1998050075A1 US 9809252 W US9809252 W US 9809252W WO 9850075 A1 WO9850075 A1 WO 9850075A1
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Prior art keywords
phenyl
group
methylsulfonyl
fluorophenyl
methyl
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PCT/US1998/009252
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English (en)
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Frank S. Caruso
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Algos Pharmaceutical Corporation
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Priority to AU74727/98A priority Critical patent/AU7472798A/en
Publication of WO1998050075A1 publication Critical patent/WO1998050075A1/fr

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    • 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
    • A61K31/13—Amines
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • 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

Definitions

  • This invention relates to a method and composition for alleviating pain. More particularly, this invention is concerned with alleviating pain by administration of a cyclooxygenase-2 inhibitor (also referred to as a cyclooxygenase ⁇ , COX-2 or COX II inhibitor), together with a nontoxic antagonist, or blocker, for the N-methyl- D-aspartate (NMDA) receptor or nontoxic substance that blocks a major intracellular consequence of NMDA receptor activation.
  • a cyclooxygenase-2 inhibitor also referred to as a cyclooxygenase ⁇ , COX-2 or COX II inhibitor
  • NMDA N-methyl- D-aspartate
  • Non-steroidal antunflammatory drugs exert most of their antunflammatory, analgesic and antipyretic activity in addition to inhibiting hormone- induced uterine contractions and certain types of cancer growth through inhibition of prostaglandin G/H synthase, also known as cyclooxygenase.
  • cyclooxygenase also known as cyclooxygenase.
  • cyclooxygenase- 1 or the constitutive enzyme as originally identified in bovine seminal vehicles. This enzyme has been cloned, sequenced and characterized from various sources including the sheep, the mouse and man.
  • cyclooxygenase- 1 is responsible for endogenous basal release of prostaglandins and is important in their physiological functions such as the maintenance of gastrointestinal integrity and renal blood flow.
  • cyclooxygenase-2 the gene for a second inducible form of cyclooxygenase, referred to as cyclooxygenase-2, has been cloned, sequenced and characterized initially from chicken, murine and human sources. Cyclooxygenase-2 is rapidly and readily inducible by a number of agents including mitogens, endotoxin, hormones, cytokines and growth factors.
  • cyclooxygenase-2 In contrast to cyclooxygenase- 1, cyclooxygenase-2, the inducible form, is mainly responsible for the pathological effects of prostaglandins where rapid induction of the enzyme would occur in response to such agents as inflammatory agents, hormones, growth factors, and cytokines. Therefore, a selective inhibitor of cyclooxygenase-2 can have similar antunflammatory, analgesic and antipyretic properties to a conventional NSAID, and in addition would inhibit hormone- induced uterine contractions and have potential anti-cancer effects.
  • Cyclooxygenase-2 inhibitors exhibit a diminished ability to induce some of the mechanism-based side effects that occur with the use of NSAIDs.
  • such inhibitors can have a reduced potential for gastrointestinal toxicity, a reduced potential for renal side effects, a reduced effect on bleeding times and possibly a dkninished ability to induce asthma attacks in aspirin-sensitive aspirin-sensitive asthmatic subjects.
  • analgesic effectiveness of a cyclooxygenase-2 inhibitor can be appreciably potentiated, or enhanced, by administration of a cyclooxygenase-2 inhibitor prior to, with or following the administration of an analgesia-potentiating amount of a nontoxic NMDA receptor antagonist and/or substance that blocks a major intracellular consequence of NMDA receptor activation.
  • a method of alleviating pain comprises administering to a mammal exhibiting pain (a) an analgesia-inducing amount of at least one cyclooxygenase-2 inhibitor and (b) an analgesia-potentiating amount of at least one analgesia-potentiator selected from the group consisting of nontoxic N-methyl-D-aspartate receptor antagonist and nontoxic substance that blocks a major intracellular consequence of N-methyl-D-aspartate receptor activation.
  • a composition for alleviating pain which comprises (a) an analgesia-inducing amount of at least one cyclooxygenase-2 inhibitor and (b) an analgesia-potentiating amount of at least one analgesia-potentiator selected from the group consisting of nontoxic N-methyl-D- aspartate receptor and nontoxic substance that blocks a major intracellular consequence of N-methyl-D-aspartate receptor activation.
  • the method of the invention and the therapeutic composition therefor are applicable to the treatment of all varieties of pain.
  • an enhanced level of analgesia for an equivalent dosage of at least one cyclooxygenase-2 inhibitor, or an equivalent level of analgesia for a reduced dosage of at least one cyclooxygenase-2 inhibitor can be achieved when at least one cyclooxygenase-2 inhibitor is administered prior to, with or following the administration of the analgesia-potentiator.
  • N-methyl-D-aspartate receptor shall be understood to include all of the binding site subcategories associated with the NMDA receptor, e.g., the glycine-binding site, the phenylcyclidine (PCP)-binding site, etc., as well as the NMDA channel.
  • PCP phenylcyclidine
  • nontoxic as used herein shall be understood in a relative sense and is intended to designate any substance that has been approved by the United States Food and Drug Administration (“FDA”) for administration to humans or, in keeping with established regulatory criteria and practice, is susceptible to approval by • the FDA for administration to humans.
  • FDA United States Food and Drug Administration
  • nontoxic is also used herein to distinguish the NMDA receptor antagonists, or blockers, that are useful in the practice of the present invention from NMDA receptor antagonists such as MK 801 (the compound 5-methyl-10,H-dihydro-SH-dibenze[a,d] cyclohepten-5,10-imine), CPP (the compound 3-[2-carboxypiperazin-4-yl] propyl-1-phosphonic acid) and PCP (the compound l-(l-phenylcyclohexyl)piperidine) whose toxicities effectively preclude their therapeutic use.
  • MK 801 the compound 5-methyl-10,H-dihydro-SH-dibenze[a,d] cyclohepten-5,10-imine
  • CPP the compound 3-[2-carboxypiperazin-4-yl] propyl-1-phosphonic acid
  • PCP the compound l-(l-phenylcyclohexyl)piperidine
  • potentiate and “potentiating” are used herein in their art- recognized sense, i.e., as referring to a significant increase in the level of pain- alleviating activity for the combination of cyclooxygenase-2 inhibitor and nontoxic NMDA receptor antagonist and/or nontoxic substance that blocks a major intracellular consequence of NMDA receptor activation compared with that which could have been expected based on the activities of the cyclooxygenase-2 inhibitor administered alone and nontoxic NMDA receptor antagonist and/or nontoxic substance that blocks a major intracellular consequence of NMDA receptor activation administered alone.
  • pain-alleviating shall be understood herein to include the expressions “pain-suppressing” and “pain-inhibiting” as the invention is applicable to the alleviation of existing pain as well as the suppression or inhibition of pain which would otherwise ensue from an imminent pain-causing event.
  • analgesia-inducing amount as applied to the cyclooxygenase-2 inhibitor employed in the therapeutic method and composition of this invention shall be understood to mean an amount of cyclooxygenase-2 inhibitor which when administered by itself or in combination with the nontoxic NMDA receptor antagonist and/or substance that blocks a major intracellular consequence of NMDA receptor activation provides significant analgesic activity.
  • cyclooxygenase-2 inhibitors heretofore used to alleviate pain can be used herein.
  • Specific cyclooxygenase-2 inhibitors that can be used in this invention are disclosed in aforementioned U.S. Patent Nos. 5,393,790, 5,409,944, 5,418,254, 5,420,343, 5,436,265, 5,474,995, 5,476,944, 5,486,534, 5,510,368, 5,521,213, 5,536,752, 5,547,975, 5,550,142, 5,552,422, 5,565,482, 5,576,339, 5,580,985, 5,585,504, 5,593,994 and 5,596,008, the contents of which are incorporated by reference herein.
  • the useful cyclooxygenase-2 inhibitors include the substituted spiro compounds of U.S. Patent No. 5,393,790, e.g. , 5-(4-fluorophenyl)-6-[4-(methylsulfonyl)phenyl]spiro[2.4]hept-5-ene, 4-[6-(4- fluorophenyl)spiro[2.4]hept-5-en-5-yl]benzenesulfonamide, 6-(4-fluorophenyl)-7-[4- (methylsulfonyl)phenyl]spiro[3.4]oct-6-ene, and the like; the sulfonamides of U.S. Patent No.
  • 5,409,944 e.g., 5-methanesulfonamido-6-(2-thienylthio)-l-indanone, 5- methanesulfonamido-6-(2-(4-methyl-l ,3-diazinylthio))-l-indanone, 5- methanesulfonamido-6-(2-thiazolylthio)-l-indanone, and the like; the 2, 3 -substituted cyclopentadienyl compounds of U.S. Patent No.
  • 5,476,944 e.g., 3,5- bis(l J-dimethylethyl)benzenethiol, trans-2-[[3 ,5-bis(l , l-dimethylethyl)henyl] hiojcyclohexanol, 3-,6-dioxabicyclo-[3J.0]hexane, and the like; the 3,4-substituted pyrazoles of U.S. Patent No.
  • Patent No. 5,576,339 e.g., l-methylsulfonyl-4-[l,l- dimethyl-4-(4-fluorophenyl)cyclopenta-2,4-dien-3-yl]benzene, 4-[4-(4-fluoropyhenyl)- l,l-dimethylcyclopenta-2,4-dien-3-yl]benzenesulfonamide, and the like; the substituted pyrazoles of U.S. Patent No.
  • 5,585,504 e.g., 3-phenyl-4-(4-methylsulfonyl)phenyl-2-(5H)- furanone, 3-(3,4-difluorophenyl)-4-(4-methylsulfonyl)phenyl)-2-(5H)-furanone, and the like; the ortho substituted phenyl compounds of U.S. Patent No.
  • nontoxic substances that block the NMDA receptor and as such are useful for enhancing the analgesic activity of a cyclooxygenase-2 inhibitor in accordance with this invention are dextromethorphan ((+)-3-hydroxy-N- methylmorphinan) and its metabolite dextrorphan ((+)-3-hydroxy-N- methylmorphinan), their mixtures and their pharmaceutically acceptable salts.
  • Other useful nontoxic substances that block the NMDA receptor include amantadine (1- aminoadamantine), memantine (3,5-dimethylaminoadamantone), pyrroloquinoline quinone and cis-4-(phosphonomethyl)-2-piperidinecarboxylic acid.
  • dextromethorphan in the form of its hydrobromide salt is preferred for use herein due to its ready availability and its established use in over- the-counter medications where it functions as a cough suppressant. While dextrorphan and its pharmaceutically acceptable salts will also provide excellent results, it is not known to be in commercial manufacture at this time.
  • a blocker for the NMDA receptor at least one nontoxic substance that blocks a major intracellular consequence of NMDA receptor activation can also be used.
  • NMDA receptor a subtype of excitatory amino acid receptors
  • the major consequences of NMDA receptor activation include the following sequences, or cascades, of events occurring within nerve cells: a) translocation and activation of protein kinases such as protein kinase C ⁇ phosphorylation of substrate proteins such as cytosolic enzymes, channel proteins, receptor proteins, etc.
  • cellular enzymes such as protein kinases
  • receptor proteins such as the NMDA receptor
  • ion channel proteins such as K+, Na+, Ca+ + channels
  • neuropeptides such as dynorphin
  • a substance that blocks the NMDA receptor will effectively prevent all of the foregoing major intracellular sequences of events from taking place.
  • a substance that interferes with translocation and activation of protein kinase C or with calmodulin induced activation of constitutive nitric oxide synthase as well as induction of inducible nitric oxide synthase is also useful for the practice of this invention.
  • Nontoxic substances that block a major intracellular consequence of NMDA receptor activation and are therefore useful in the practice of the invention include inhibitors of protein kinase C, e.g., gangliosides such as ganglioside GM t (monosialoganglioside) and ganglioside GT lb (trisialoganglioside); amphipathic long chain bases such as sphingosine, N,N,N-trimethylsphingosine, sphinganine and psychosine; quinolyloxazole-2-ones such as 4-methyl-5-(3-quinolinyl)-2-(3H)- oxazolone and phenyl-5-(2-quinolinyl)-2-3(3H)-oxazolone; l,4-bis-(amino- hydroxyalkylamino)-anthraquinones such as l,4-bis-(3-propylamino-2- hydroxypropylamin
  • Additional nontoxic substances that block a major intracellular consequence of NMDA receptor activation and as such are useful in the practice of the invention include inhibitors of calmodulin such as the phenothiazines, in particular, chlorpromazine, chlorpromazine sulfoxide, prochlorperazine dimaleate, perphenazine, trifluoperazine, fluphenazine, fluphenazine enanthate, fluphenazine decanoate, thioridazine, mesoridazine besylate, piperacetazine, acetophenazine dimaleate, carphenazine dimaleate, butaperazine dimaleate and phenothiazine sulfoxide; naphthalenesulfonamides such as N-(6-aminohexyl)-5-chloro-l- naphthalenesulfonamide, N-(6-aminohexyl)-5-chloro-2-
  • the nontoxic NMDA receptor antagonists are preferred and of these, dextromethorphan is preferred for the reasons previously stated.
  • the cyclooxygenase-2 inhibitor must be present in an analgesia-inducing amount, e.g., at a level corresponding to the generally recommended adult human dosages for a particular cyclooxygenase-2 inhibitor, and the nontoxic NMDA receptor antagonist or substance that blocks a major intracellular consequence of NMDA activation must be present at a level that potentiates the analgesia-inducing effectiveness of the cyclooxygenase-2 inhibitor.
  • cyclooxygenase-2 inhibitor and nontoxic NMDA receptor antagonist and/or substance that blocks a major intracellular consequence of NMDA receptor activation need not be administered together, they must both be present in the patient at effective levels at the same time. While it is within the scope of the invention to administer the cyclooxygenase-2 inhibitor and nontoxic NMDA receptor antagonist and/ or substance that blocks a major intracellular consequence of NMDA receptor activation separately, as a matter of convenience, it is preferred that they be coadministered as a single therapeutic composition. All modes of administrations are contemplated, e.g.
  • formulations may, where appropriate, be conveniently presented in discrete dosage units and may be prepared by any of the methods well known in the art of pharmacy.
  • a therapeutic composition containing the cyclooxygenase-2 inhibitor and nontoxic NMDA receptor antagonist and/or substance that blocks a major intracellular consequence of NMDA receptor activation will ordinarily be formulated with one or more pharmaceutically acceptable ingredients in accordance with known and established practice.
  • the composition can be formulated as a liquid, powder, elixir, injectable solution, etc.
  • Formulations for oral use can be provided as tablets or hard capsules wherein the pharmacologically active ingredients are mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredients are mixed with water or miscible solvents such as propylene glycol; PEG's and ethanol, or an oleaginous medium, e.g., peanut oil, liquid paraffin or olive oil.
  • the pharmaceutical compositions may take the form of buccal or sublingual tablet, drops or lozenges formulated in conventional manner.
  • the compounds of the invention may be formulated as creams, gels, ointments or lotions or as transdermal patches.
  • Such compositions may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening, gelling, emulsifying, stabilizing, dispersing, suspending, and/or coloring agents.
  • the compounds of the invention 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.
  • the compounds of the invention may be formulated for parenteral administration by injection, conveniently intravenous, intramuscular or subcutaneous injection, for example by bolus injection or continuous intravenous infusion.
  • parenteral administration by injection, conveniently intravenous, intramuscular or subcutaneous injection, for example by bolus injection or continuous intravenous infusion.
  • For- mulations for injection may be presented in unit dosage from e.g. in ampoules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
  • the compounds of the invention may also be formulated in rectal compositions such as suppositories or retention enemas, e.g. containing conventional suppository bases such as cocoa butter or other glyceride.
  • the compounds of the invention may be used, for example, as a liquid spray, as a powder or in the form of drops.
  • the compounds according to the invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g. dichlo- rodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, tetrafluoroethane, heptafluoropropane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g. dichlo- rodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, tetrafluoroethane, heptafluoropropane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g. dichlo- rodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, tetrafluoroethane, heptafluor
  • Aqueous suspensions can include pharmaceutically acceptable excipients such as suspending agents, e.g., sodium carboxymethyl cellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as naturally occurring phosphatide, e.g. , lecithin, or condensation products of an alkylene oxide with fatty acids, e.g., polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, e.g, heptadecaethylene-oxycetanol, or condensation products of ethylene oxide with.
  • suspending agents e.g., sodium carboxymethyl cellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia
  • dispersing or wetting agents such as naturally occurring phosphatide, e.g. ,
  • partial esters derived from fatty acids and a hexitol e.g., polyoxyethylene sorbitol monoleate or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, e.g., polyoxyethylene sorbitan monoleate.
  • the aqueous suspensions can also contain one or more preservatives, e.g., ethyl-or-n-propyl-p-hydroxy benzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose, saccharin or sodium or calcium cyclamate.
  • the therapeutic composition herein can contain at least one other pharmacologically active substance, e.g.
  • a non-narcotic analgesic such as tramadol, acetaminophen, aspirin, diclofenac, diflusinal, etodolac, fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, nabumetone, naproxen, oxaprozin, phenylbutazone, piroxicam, sulindac, tolmetin, zomepirac, and the like, or a narcotic analgesic such as codeine, oxycodone, dihydrocodeine, hydrocodone, levorphanol, morphine, and the like.
  • a narcotic analgesic such as codeine, oxycodone, dihydrocodeine, hydrocodone, levorphano
  • Example Cvclooxygenase-2 Inhibitor (mg) Blocker (mg) Component (mg) 33 5-(4-(methylsulfonyl)phenyl)-6-phenylimidazo dextromethorphan
  • the nontoxic NMDA receptor antagonist dextromethorphan hydrobromide significantly potentiates the pain-alleviating activity of the cyclooxygenase-2 inhibitor.

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Abstract

L'efficacité analgésique d'un inhibiteur de cyclo-oxygénase-2 (COX-2) se trouve grandement améliorée par l'administration dudit inhibiteur avec un antagoniste non toxique de récepteur N-méthyl-D-aspartate et/ou une substance non toxique qui bloque au moins une conséquence intracellulaire majeure de l'activation du récepteur N-méthyl-D-aspartate.
PCT/US1998/009252 1997-05-07 1998-05-06 Inhibiteurs de cox-2 en combinaison avec des agents bloquants le nmda pour traiter la douleur WO1998050075A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU74727/98A AU7472798A (en) 1997-05-07 1998-05-06 Cox-2 inhibitors in combination with nmda-blockers for treating pain

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US4591497P 1997-05-07 1997-05-07
US60/045,914 1997-05-07

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Publication Number Publication Date
WO1998050075A1 true WO1998050075A1 (fr) 1998-11-12

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Cited By (24)

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WO2000029023A1 (fr) * 1998-11-12 2000-05-25 Algos Pharmaceutical Corporation Utilisation d'une combinaison d'inhibiteurs de cox-2 et de substances bloquant les recepteurs de nmda pour le traitement de la douleur
WO2000029022A1 (fr) * 1998-11-12 2000-05-25 Algos Pharmaceutical Corporation Combinaison d'inhibiteurs de cox-2 et d'analgesiques a action centrale
WO2000051685A1 (fr) * 1999-03-01 2000-09-08 Ortho-Mcneil Pharmaceutical, Inc. Composition comprenant du tramadol et un medicament inhibiteur selectif de cox-2
US6294558B1 (en) 1999-05-31 2001-09-25 Pfizer Inc. Sulfonylbenzene compounds as anti-inflammatory/analgesic agents
DE10059020A1 (de) * 2000-11-28 2002-05-29 Gruenenthal Gmbh Parenteral applizierbare Darreichungsformen
US6727238B2 (en) 1998-06-11 2004-04-27 Pfizer Inc. Sulfonylbenzene compounds as anti-inflammatory/analgesic agents
WO2004039371A2 (fr) * 2002-10-29 2004-05-13 Pharmacia Corporation Compositions d'inhibiteurs selectifs de la cyclooxygenase-2 et d'antagonistes du recepteur nmda destinees au traitement ou a la prevention de douleurs neuropathiques
WO2008055945A1 (fr) 2006-11-09 2008-05-15 Probiodrug Ag Dérivés 3-hydr0xy-1,5-dihydr0-pyrr0l-2-one utiles en tant qu' inhibiteurs de la glutaminyl-cyclase dans le traitement des ulcères, du cancer et d'autres maladies
WO2008065141A1 (fr) 2006-11-30 2008-06-05 Probiodrug Ag Nouveaux inhibiteurs de glutaminylcyclase
WO2008104580A1 (fr) 2007-03-01 2008-09-04 Probiodrug Ag Nouvelle utilisation d'inhibiteurs de la glutaminyl cyclase
US7732162B2 (en) 2003-05-05 2010-06-08 Probiodrug Ag Inhibitors of glutaminyl cyclase for treating neurodegenerative diseases
WO2011029920A1 (fr) 2009-09-11 2011-03-17 Probiodrug Ag Dérivés hétérocycliques en tant qu'inhibiteurs de glutaminyle cyclase
WO2011107530A2 (fr) 2010-03-03 2011-09-09 Probiodrug Ag Nouveaux inhibiteurs
WO2011110613A1 (fr) 2010-03-10 2011-09-15 Probiodrug Ag Inhibiteurs hétérocycliques de la glutaminyl cyclase (qc, ec 2.3.2.5)
WO2011131748A2 (fr) 2010-04-21 2011-10-27 Probiodrug Ag Nouveaux inhibiteurs
WO2012123563A1 (fr) 2011-03-16 2012-09-20 Probiodrug Ag Dérivés de benzimidazole en tant qu'inhibiteurs de la glutaminyl cyclase
US8309570B2 (en) 2001-06-07 2012-11-13 Analgesic Neuropharmaceuticals, Llc Treatment of central neuropathic pain
US8541471B2 (en) 2003-05-07 2013-09-24 Osteologix A/S Water-soluble strontium salts for use in treatment of cartilage and/or bone conditions
EP2865670A1 (fr) 2007-04-18 2015-04-29 Probiodrug AG Dérivés de thio-urée utilisés comme inhibiteurs de la glutaminyl cyclase
US9492444B2 (en) 2013-12-17 2016-11-15 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
US9707184B2 (en) 2014-07-17 2017-07-18 Pharmaceutical Manufacturing Research Services, Inc. Immediate release abuse deterrent liquid fill dosage form
US10172797B2 (en) 2013-12-17 2019-01-08 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
US10195153B2 (en) 2013-08-12 2019-02-05 Pharmaceutical Manufacturing Research Services, Inc. Extruded immediate release abuse deterrent pill
EP3461819A1 (fr) 2017-09-29 2019-04-03 Probiodrug AG Inhibiteurs de la glutaminyl-cyclase

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WO2000051685A1 (fr) * 1999-03-01 2000-09-08 Ortho-Mcneil Pharmaceutical, Inc. Composition comprenant du tramadol et un medicament inhibiteur selectif de cox-2
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