+

WO2000029023A1 - Cox-2 inhibitors in combination with nmda-blockers for treating pain - Google Patents

Cox-2 inhibitors in combination with nmda-blockers for treating pain

Info

Publication number
WO2000029023A1
WO2000029023A1 PCT/US1998/024317 US9824317W WO0029023A1 WO 2000029023 A1 WO2000029023 A1 WO 2000029023A1 US 9824317 W US9824317 W US 9824317W WO 0029023 A1 WO0029023 A1 WO 0029023A1
Authority
WO
WIPO (PCT)
Prior art keywords
phenyl
methylsulfonyl
fluorophenyl
group
methyl
Prior art date
Application number
PCT/US1998/024317
Other languages
French (fr)
Inventor
Frank S. Caruso
Original Assignee
Algos Pharmaceutical Corporation
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 Algos Pharmaceutical Corporation filed Critical Algos Pharmaceutical Corporation
Priority to AU14086/99A priority Critical patent/AU1408699A/en
Priority to EP98957950A priority patent/EP1146905A1/en
Priority to JP2000582069A priority patent/JP2002538078A/en
Priority to PCT/US1998/024317 priority patent/WO2000029023A1/en
Priority to CA002351224A priority patent/CA2351224A1/en
Publication of WO2000029023A1 publication Critical patent/WO2000029023A1/en

Links

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
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • 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
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • 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
    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • 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
    • A61K31/60—Salicylic acid; Derivatives thereof
    • 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
    • A61P25/06—Antimigraine agents
    • 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]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • This invention relates to a method for alleviating a pain state not associated with a cough condition, i.e., arthritic pain, post-operative pain, lumbosacral pain, musculo-skeletal pain, headache or migraine, by administering to a mammal in need of relief from a pain state not associated with a cough condition a cyclooxygenase-2 inhibitor (also referred to as a cyclooxygenase II, 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 II, COX-2 or COX II inhibitor
  • NMDA N-methyl-D- aspartate
  • Non-steroidal antiinflammatory drugs exert most of their antiinflammatory, 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.
  • prostaglandin G/H synthase also known as cyclooxygenase.
  • cyclooxygenase- 1 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.
  • prostaglandins have both physiological and pathological roles
  • 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. 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 antiinflammatory, 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 are known. See, e.g., U.S. Patent Nos. 5,393,790; 5,409,944; 5,418,254; 5,420,343; 5,436,265; 5,466,823; 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; 5,596,008; 5,604,253; 5,604,260; 5,639,780; 5,677,318; 5,691,374; 5,698584; 5,710,140; 5,733,909; 5,767,291 ; 5,789,413 and 5,817,700.
  • 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 diminished ability to induce asthma attacks in aspirin-sensitive aspirin-sensitive asthmatic subjects.
  • Dextromethorphan is the d-isomer of the codeine analog of levorphanol.
  • dextromethorphan is said to have no analgesic or addictive properties (Goodman and Gilman's, "The Pharmacological Basis of Therapeutics", 8 th ed., McGraw-Hill, Inc. (1990), p. 518)
  • a method of alleviating a pain state not associated with a cough condition comprises administering to a mammal exhibiting a pain state not associated with a cough condition (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.
  • the method of this invention is applicable to the treatment of all varieties of pain other than one associated with a cough condition, e.g., arthritic pain and other forms of chronic pain such as neuropathic pain, post-operative pain, lumbosacral pain, musculo-skeletal pain, headache, migraine, and the like.
  • a cough condition e.g., arthritic pain and other forms of chronic pain such as neuropathic pain, post-operative pain, lumbosacral pain, musculo-skeletal pain, headache, migraine, and the like.
  • 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.
  • the invention herein contemplates the use of nontoxic substances that block an NMDA receptor binding site, e.g. , dextromethorphan, or that block the NMDA channel, e.g., a source of magnesium such as magnesium sulfate.
  • 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,l l-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,l l-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.
  • the term "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 method 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.
  • any of the 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; 5,418,254;
  • 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-
  • 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 ,l- dimethylethyl)benzenethiol, trans-2-[[3 ,5-bis(l , 1 -dimethylethyl)henyl] hiOjCyclohexanol, 3,6-dioxabicyclo-[3.1.0]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- ⁇ henyl-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.
  • 5,639,780 e.g., [4-(l-(4-Bromobenzyl)-5-methoxy-2- methyl-l-H-indol-3-yl)-3-(ethane-l ,2-diyl)]butanoic acid, 4-(l-(4-Bromobenzyl)-5- methoxy-2-methyl-l-H-indol-3-yl)-2-methylbutanoic acid and the like; the diphenyl- 1,2-3-thiadiazoles of U.S. Patent No.
  • 5,691,374 e.g., 5-hydroxy-3-(3,4-difluorophenyl)-4-(4- (methylsulfonyl)phenyl)-2-(5H)-furanone, 5-hydroxy-5-methyl-,4-(4- (methylsulfonyl)phenyl)-3-phenyl-2-(5H)-furanone, 5-hydroxy-4-(4-
  • Patent No. 5,733,909 e.g. , (E)-3-(4-methylsulfonyl)phenyl-2-phenylbut-2-enoic acid methyl ester, (E)-3-(methylsulfonyl)phenyl-2-phenylbut-2-enoic acid, (E)-3-(4- methylsulfonyl)phenyl-l-morpholin-4-yl-2-phenylbut-2en-l-one and the like; the alkylated styrenes of U.S. Patent No.
  • 5,817,700 e.g., 4,4-dichloro-3-(4-methylthiophenyl)-2-phenyl-2-cyclobuten-l-one, 4,4-dichloro-3-(4- methylsulfonylphenyl)-2-phenyl-2-cyclobuten-l-one, 4-chloro-3-(4- methylsulfonylphenyl)-2-phenyl-2-cyclobuten-l-one and the like and MK-966 (which is also referred to by Merk & Co. as "VIOXX").
  • 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.
  • ⁇ changes in functional activity b) initiation of early gene (c-fos, c-jun, zif-268, etc.) expression by either increased intracellular Ca+ + or Ca+ + -activated protein kinases ⁇ expression of functional genes responsible for production of 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), 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, (monosialoganglioside) and ganglioside GT, b (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; 1 ,4-bis-(amino- hydroxyalkylamino)-anthraquinones such as 1 ,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 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., orally, rectally, parenterally, topically, or by intravenous, intramuscular, intrastemal or subcutaneous injection or in a form suitable by inhalation.
  • the 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.
  • analgesic 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.
  • an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin
  • water or miscible solvents such as propylene glycol; PEG's and ethanol
  • an oleaginous medium e.g., peanut oil, liquid paraffin or olive oil.
  • the analgesic compositions can take the form of buccal or sublingual tablet, drops or lozenges formulated in conventional manner.
  • compositions can, 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 can also be formulated as depot preparations. Such long acting formulations can be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds can 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.
  • suitable polymeric or hydrophobic materials for example as an emulsion in an acceptable oil
  • ion exchange resins for example as sparingly soluble derivatives, for example as a sparingly soluble salt.
  • the compounds of the invention can be formulated for parenteral administration by injection, conveniently intravenous, intramuscular or subcutaneous injection, for example by bolus injection or continuous intravenous infusion.
  • Formulations for injection can be presented in unit dosage from e.g. in ampoules or in multi-dose containers, with an added preservative.
  • compositions can take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and can 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.
  • a suitable vehicle e.g. sterile pyrogen-free water
  • the compounds of the invention can 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 can 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
  • 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.
  • 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 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.
  • 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 can be administrered with the cylooxygenase-2 inhibitor and nontoxic NMDA receptor antagonist and/or substance that blocks a major intracellular
  • the nontoxic NMDA receptor antagonist dextromethorphan hydrobromide significantly potentiates the pain-alleviating activity of the cyclooxygenase-2 inhibitor.

Landscapes

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

Abstract

A method of alleviating a pain state not associated with a cough condition is provided which comprises administering to a mammal exhibiting a pain state not associated with a cough condition a cyclooxygenase-2 inhibitor with a nontoxic NMDA receptor antagonist and/or a nontoxic substance that blocks at least one major intracellular consequence of NMDA receptor activation.

Description

COX-2 INHIBITORS IN COMBINATION WITH NMDA-BLOCKERS FOR TREATING PAIN
BACKGROUND OF THE INVENTION This invention relates to a method for alleviating a pain state not associated with a cough condition, i.e., arthritic pain, post-operative pain, lumbosacral pain, musculo-skeletal pain, headache or migraine, by administering to a mammal in need of relief from a pain state not associated with a cough condition a cyclooxygenase-2 inhibitor (also referred to as a cyclooxygenase II, 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.
Non-steroidal antiinflammatory drugs (NSAIDS) exert most of their antiinflammatory, 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. Initially, only one form of cyclooxygenase was known, this corresponding to 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. As prostaglandins have both physiological and pathological roles, 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.
More recently, 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. 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 antiinflammatory, analgesic and antipyretic properties to a conventional NSAID, and in addition would inhibit hormone-induced uterine contractions and have potential anti-cancer effects.
A number of cyclooxygenase-2 inhibitors are known. See, e.g., U.S. Patent Nos. 5,393,790; 5,409,944; 5,418,254; 5,420,343; 5,436,265; 5,466,823; 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; 5,596,008; 5,604,253; 5,604,260; 5,639,780; 5,677,318; 5,691,374; 5,698584; 5,710,140; 5,733,909; 5,767,291 ; 5,789,413 and 5,817,700. Cyclooxygenase-2 inhibitors exhibit a diminished ability to induce some of the mechanism-based side effects that occur with the use of NSAIDs. In particular, 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 diminished ability to induce asthma attacks in aspirin-sensitive aspirin-sensitive asthmatic subjects. Dextromethorphan is the d-isomer of the codeine analog of levorphanol.
Unlike the 1-isomer, dextromethorphan is said to have no analgesic or addictive properties (Goodman and Gilman's, "The Pharmacological Basis of Therapeutics", 8th ed., McGraw-Hill, Inc. (1990), p. 518)
Each of U.S. Patent Nos. 5,409,944; 5,436,265; 5,474,995; 5,510,368; 5,521,213; 5,536,752; 5,550,142; 5,552,422; 5,604,253; 5,604,260; 5,639,780; 5,677,318; 5,691,374; 5,698584; 5,710,140; 5,733,909; 5,767,291; 5,789,413 and 5,817,700 describe a composition containing a cyclooxygenase-2 inhibitor in combination with a nonopioid antitussive such as dextromethorphan, caramiphen or carbetapentane, or an opioid antitussive such as codeine or hydrocodone. However, there is not even a remote suggestion that the combination of a cyclooxygenase-2 inhibitor and an antitussive can be used to treat pain which is not associated with a cough condition.
SUMMARY OF THE INVENTION
In accordance with the present invention, a method of alleviating a pain state not associated with a cough condition is provided with comprises administering to a mammal exhibiting a pain state not associated with a cough condition (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.
The method of this invention is applicable to the treatment of all varieties of pain other than one associated with a cough condition, e.g., arthritic pain and other forms of chronic pain such as neuropathic pain, post-operative pain, lumbosacral pain, musculo-skeletal pain, headache, migraine, and the like. Thus, for a mammal in need of pain relief except where the pain state being treated is one accompanied by a cough condition, 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. The expression "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. Thus, the invention herein contemplates the use of nontoxic substances that block an NMDA receptor binding site, e.g. , dextromethorphan, or that block the NMDA channel, e.g., a source of magnesium such as magnesium sulfate. The term "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. The term "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,l l-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.
The terms "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. The term "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. The expression "analgesia-inducing amount" as applied to the cyclooxygenase-2 inhibitor employed in the method 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.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
By way of alleviating a pain state not associated with a cough condition, any of the 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; 5,418,254;
5,420,343; 5,466,823; 5,476,944; 5,486,534; 5,547,975; 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. More particularly, 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. 5,418,254, e.g., l-methylsulfonyl-4- [1 , l-dimethyl-4-(4-fluorophenyl)cyclopenta-2,4-dien-3-yl]benzene, 4-[4-(4- fluorophenyl)-l ,l-dimethylcyclopenta-2,4-dien-3-yl]benzenesulfonamide, 1- methylsulfonyl-4-{4-(4-trifluoromethylphenyl)-l-trifluoromethylcyclopenta-2,4-dien-3- yljbenzene, and the like; the aromatic cycloethers of U.S. Patent No. 5,420,343, e.g., methyl 3 , 5-bis( 1 , 1 -dimethylethyl)benzoate , 3 , 5-bis( 1 , 1 -dimethylethyl) benzenemethanol, l,3-bis(l,l-dimethylethyl)-5-(2-chloroethyl)benzene, and the like; the 1-aroyl acids of U.S. Patent No. 5,436,265, e.g., l-(2,4,6-trichlorobenzoyI)-5- methoxy-2-methyl-3-indolyl acetic acid, l-(2,6-dichlorobenzoyl)-5-methoxy-2-methyl- 3-indolyl acetic acid and the like; the phenyl heterocycles of U.S. Patent Nos. 5,474,995, 5,536,752, 5,550,142, 5,710,140 and 5,767,291, e.g., 3-(4- (aminosulfonyl)phenyl)-2-(4-fluorophenyl)thiophene, 2-(4-fluorophenyl)-3-(4- (methylsulfonyl)phenyl)-2-cyclopentenone, 4-(4-methylsulfonyl)phenyl)-5-(4- fluorophenyl)isothiazole, , 4-(aminosulfonyl)phenyl)-2-(4-fluorophenyl)thiophene, 3- (4-(aminosulfonyl)phenyl)-2-4-(fluorophenyl)-5-(2-propyl)thiophene, 3-(4-
(aminosulfonyl)phenyl)-2-cyclohexylthiophene, 3-(4-(aminosulfonyl)phenyl)-2-4- (fluorophenyl)-5-(2-hydroxy-2-propyl)thiophene, 3-(4-(aminosulfonyl)phenyl)-2-(4- fluorophenyl)thiophene and the like; the benzenesulfonamides of U.S. Patent No. 5,466,823, e.g. , 4-(5-(4-methylphenyl)-3-(trifluoromethyl)-lH-pyrazol-l- yl)benzenesulfonamide (which is also referred to as celecoxib) and the like; the cyclic phenolic thioether derivatives of U.S. Patent No. 5,476,944, e.g., 3,5-bis(l ,l- dimethylethyl)benzenethiol, trans-2-[[3 ,5-bis(l , 1 -dimethylethyl)henyl] hiOjCyclohexanol, 3,6-dioxabicyclo-[3.1.0]hexane, and the like; the 3,4-substituted pyrazoles of U.S. Patent No. 5,486,534, e.g., 4-(4-fluorophenyl)-l-methyl-3-[4- (methylsulfonyl)phenyl]-5-trifluoromethyl)pyrazole, 1 -benzyl-4-(4-fluorophenyl)-3-[4- (methylsulfonyl)phenyl]-5-(trifluoromethyl)pyrazole, l-allyl-4(4-fluorophenyl)-3-[4- methylsulfonyl)phenyl]-5-(trifluoromethyl)-lH-pyrazole, and the like; the N-benzyl-3- indoleacetic acids of U.S. Patent No. 5,510,368, e.g., 2-(5-bromo-l-(4-bromobenzyl)- 2-methyl-lH-indol-3-yl)propionic acid, (S)-(+)-2-(5-bromo-l-(4-bromophenyl)-2- methyl-lH-indol-3-yl)acetyl acid, (R)-(-)-2-(5-bromo-l-(4-bromobenzyl)-2-methyl-lH- indol-3-yl)propionic acid, and the like; the diaryl bicyclic heterocyclics of U.S. Patent No. 5,521,213, e.g., 3-(4-(methylsulfonyl)phenyl)-2-phenylbenzo[b]furan, 3-(4- (methanesulfonyl)phenyl)-2-phenylbenzo[b]thiophene, 2-(4-fluorophenyl)-3-(4- aminosulfonyl)phenyl)-4H-thieno[2,3-c]furan-6-one, and the like; the benzopyranopyrazolyl derivatives of U.S. Patent No. 5,547,975, e.g. , 4-[l ,4-dihydro- 3-(trifluoromethyl)-[l]benzopyrano[4,3-c]pyrazol-l-yl]benzenesulfonamide, methyl[l- [4-(aminosulfonyl)phenyl]-l,4-dihydro-[l]benzopyrano[4,3-c]pyrazol-3-yl] carboxylate, 4-[3-(trifluoromethyl)- 1 H-benzofuro[3 ,2-c]pyrazol- 1 -yl] benzenesulfonamide, and the like; the aryl substituted 5,5 fused aromatic nitrogen compounds of U.S. Patent No. 5,552,422, e.g., 5-(4-methylsulfonyl)phenyl)-6- phenylimidazo[2,l-bjthiazole, 2-methyl-5-(methylsulfonyl)phenyl)-6- phenylimidazo[2,l-b]thiazole, 3-methyl-5-(4-methylsulfonyl)phenyl)-6- phenylimidazo[2,l-b]thiazole, and the like; the heteroarylpyranopyrazolyl derivatives of U.S. Patent No. 5,565,482, e.g., 4-[l,5-dihydro-6-fluoro-7-methoxy-3- (trifluoromethyl)-[2]benzothiopyrano[4,3-c]pyrazol, 4-[l ,4-dihydro-3-(trifluoromethyl)- [l]benzopyrano-[4,3-c]pyrazol-l-yl]benzenesulfonamide, l,5-dihydro-6-fluoro-7- methoxy-l-[(4-methylsulfonyl)phenyl]-3-(trifluoromethyl)-[2]benzothiopyrano-[4,3- c]pyrazol-l-yl]benzenesulfonamide, and the like; the pyridyl substituted cyclopentadienes of U.S. 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. 5,580,985, e.g., l-ethyl-4-(4-fluorophenyl)-3-[4- (methylsulfonyl)phenyl]-5-(trifluoromethyl)-lH-pyrazole, 3-amino-4,4,4-trifluoro-2(4- fluorophenyl)-l-[4-(methylthio)phenyl]-2-buten-l-one, l-benzyl-4-(4-fluorophenyl)-3- [4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)pyrazole, and the like; the lactones of U.S. Patent No. 5,585,504, e.g., 3-ρhenyl-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. 5,593,994, e.g., 2- [(4-methylthio)phenyl]-l-biphenyl,l-cyclohexene-2-(4'-methylsulfonylphenyl) benzene, 3-(4'-methylsulfonylphenyl)-4-phenylphenol, and the like; the 3,4-diaryl substituted pyridines of U.S. Patent No. 5,596,008, e.g., 5-(4-fluorophenyl)-2-methoxy-4-[4- (methylsulfonyl)phenyl]-6-(trifluoromethyl)pyridine, 2-ethoxy-5-(4-fluorophenyl)-4-[4- (methylsulfonyl)phenyl]-6-(trifluoromethyl)pyridine, 5-(4-fluorophenyl)-4-[4- (methylsulfonyl)phenyl]-2-(2-propynyloxy)-6-(trifluoromethyl)pyridine, and the like; the N-benzylindol-3-yl propanoic acid derivatives of U.S. Patent No. 5,604,253, e.g. , 3-[l-(p-Bromobenzyl)-5-methoxy-2-methylindol-3-yl]propanoic acid, 3-[l-(p-
Bromobenzyl)-5-methoxy-2-methylindol-3-yl]-2,2-dimethyl-propanoic acid, 2-Benzyl- 3-[l-(p-Bromobenzyl)-5-methoxy-2-methylindol-3-yl]propanoic acid and the like; the 5-methanesulfonamido-l-indanones of U.S. Patent No. 5,604,260, e.g. , 4-(2,4- Dichlorophenoxy)-3-nitrobenzaldehyde, 5-methanesulfonamido-6-(2,4- difluorophenylthio)-l-indanone and the like; the N-benzylindol-3-yl butanoic acid derivatives of U.S. Patent No. 5,639,780, e.g., [4-(l-(4-Bromobenzyl)-5-methoxy-2- methyl-l-H-indol-3-yl)-3-(ethane-l ,2-diyl)]butanoic acid, 4-(l-(4-Bromobenzyl)-5- methoxy-2-methyl-l-H-indol-3-yl)-2-methylbutanoic acid and the like; the diphenyl- 1,2-3-thiadiazoles of U.S. Patent No. 5,677,318, e.g., 4-Phenyl-5-(4- (methylsulfonyl)-phenyl-l ,2,3-thiadiazole, 4-(4-fluorophenyl)-5-(4- (methylsulfonyl)phenyl-l ,2,3-thiadiazole, 4-(3-fluorophenyl)-5-(4- (methylsulfonyl)phenyl-l ,2,3-thiadiazole and the like; the diaryl-5-oxygenated-2-(5H)- furanones of U.S. Patent No. 5,691,374, e.g., 5-hydroxy-3-(3,4-difluorophenyl)-4-(4- (methylsulfonyl)phenyl)-2-(5H)-furanone, 5-hydroxy-5-methyl-,4-(4- (methylsulfonyl)phenyl)-3-phenyl-2-(5H)-furanone, 5-hydroxy-4-(4-
(methylsulfonyl)phenyl)-3-phenyl-2-(5H)-furanone and the like; the 3,4-diaryl-2- hydroxy-2,5-dihydrofuranes of U.S. Patent No. 5,698,584, e.g., 3-(3,5- difluorophenyl)-5,5-dimethyl-2-hydroxy-4-(4-(methylsulfonyl)phenyl)-2,5- dihydrofuran, 5,5-dimethyl-3-(4-fluorophenyl)-2-hydroxy-4-(4- (methylsulfonyl)phenyl)-2,5-dihydrofuran, 5,5-dimethyl-2-ethoxy-3-(3-fluorophenyl)- 4-(4-(methylsulfonyl)phenyl)-2,5-dihydrofuran and the like; the diphenyl stilbenes of U.S. Patent No. 5,733,909, e.g. , (E)-3-(4-methylsulfonyl)phenyl-2-phenylbut-2-enoic acid methyl ester, (E)-3-(methylsulfonyl)phenyl-2-phenylbut-2-enoic acid, (E)-3-(4- methylsulfonyl)phenyl-l-morpholin-4-yl-2-phenylbut-2en-l-one and the like; the alkylated styrenes of U.S. Patent No. 5,789,413, e.g., 2-(3-fluorophenyl)-4-methyl-3- (4-(methylsulfonyl)-phenyl)-2-(Z)-penten-1.4-diol, acetic acid 4-acetoxy-2-(3- fluorophenyl)-4-methyl-3-(4-(methylsulfonyl)phenyl)-2-(Z)-pent-2-enyl ester, 2-(3- fluorophenyl)-4-methoxy-4-methyl-3-((4-methylsulfonyl lphenyl)-2-(Z)-pentenoic acid and the like; the bisaryl cyclobutene derivatives of U.S. Patent No. 5,817,700, e.g., 4,4-dichloro-3-(4-methylthiophenyl)-2-phenyl-2-cyclobuten-l-one, 4,4-dichloro-3-(4- methylsulfonylphenyl)-2-phenyl-2-cyclobuten-l-one, 4-chloro-3-(4- methylsulfonylphenyl)-2-phenyl-2-cyclobuten-l-one and the like and MK-966 (which is also referred to by Merk & Co. as "VIOXX").
Among the 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. Of the nontoxic NMDA receptor antagonists, 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. In addition to, or in place of, 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. Activation of the NMDA receptor, a subtype of excitatory amino acid receptors, induces a number of changes in the functional activity of nerve cells and, in particular, their capacity for excitability or inhibition in the presence of an addictive substance via an increase in intracellular Ca+ + concentration. 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. → changes in functional activity; b) initiation of early gene (c-fos, c-jun, zif-268, etc.) expression by either increased intracellular Ca+ + or Ca+ + -activated protein kinases → expression of functional genes responsible for production of 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), etc. → changes in functional activity; c) Ca+ +/calmodulin (or other Ca+ + binding proteins) induced activation of enzymes and other cellular components → activation of Ca+ -f-/calmodulin-protein kinase systems such as Ca+ +/calmodulin kinase II → autophosphorylation of enzymes (e.g., Ca+ +/calmodulin kinase II) or other functional proteins → changes in functional activity; d) Ca+ +/calmodulin induced activation of constitutive nitric oxide synthase as well as induction of inducible nitric oxide synthase → production of nitric oxide → i) production of cyclic guanosine monophosphate via activation of guanosine cyclase resulting in activation of protein kinases and early gene expression; ii) direct protein modification such as enzymes, receptor and/or channel proteins; iii) lipid membrane modification and/or nucleic acid modification via scavenge of free radicals; iv) induction of neurotoxicity at higher nitric oxide levels; v) retrograde actions in adjacent neurons or glial cells such as facilitation of glutamate release/NMDA receptor activation and/or inhibition of post-synaptic NMDA receptors → changes in functional activity; e) interactions with the cyclic adenosine monophosphate/protein kinase A system, the phospholipase C-inositol triphosphate-Ca-r- - /diacylglycerol- protein kinase system, the phospholipase A2-arachidonic acid/prostanoids/ leukotrienes system → changes in functional activity induced by second messenger systems other than NMDA receptor/Ca++/Ca++-calmodulin/protein kinase systems; and, f) interactions with other excitatory amino acid receptor subtypes including non-NMDA receptors and metabotropic receptors as well as intracellular events subsequent to the activation of these excitatory amino acid receptor subtypes → changes in functional activity induced by the non-NMDA and metabotropic receptor activation.
A substance that blocks the NMDA receptor will effectively prevent all of the foregoing major intracellular sequences of events from taking place. However, even with activation of the NMDA receptor, it is still possible to treat neuropathic pain in accordance with this invention by administering the cyclooxygenase-2-inhibitor and a nontoxic substance that blocks at least one of the foregoing major intra-cellular sequences of events brought about by activation of the NMDA receptor. Thus, e.g. , 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, (monosialoganglioside) and ganglioside GT,b (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; 1 ,4-bis-(amino- hydroxyalkylamino)-anthraquinones such as 1 ,4-bis-(3-propylamino-2- hydroxypropylamino)-9,10 anthracenedione and 1 ,4-bis-(3-benzylamino-2- hydroxypropylamino)-9,10 anthracenedione; and, mixtures and pharmaceutically acceptable salts of any of the foregoing.
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-naphthalenesulfonamide and N- (6-aminohexyl)-5-bromo-2-naphthalenesulfonamide ; 4-substituted-4H , 6H-pyrrolo[ 1 , 2- a][4.1] benzoxazepines such as l,3-dihydro-l-{l-[(4-methyl-4H,6H-pyrrolo[l ,2-a][4,l] benzoxazepin-4-yl)methyI]-4-piperidinyl}-2H-benzimidazol-2-one; benzhydryls such as N- [2] (dipheny lmethy Ithioethyl] -2-(trifluoromethyl)-benzeneethanamine , N- [2-(bis(4- fluorophenyl)methylthio)- ethyl]-2-(trifluoromethyl)benzeneethanamine and N-[2- (bis(4-fluorophenyl)methylthio)ethyl]-3-(trifluoromethyl)benzene-ethanamine; tricyclic antidepressant drugs such as imipramine, 2-chloroimipramine and amitriptyline; penfluridol; haloperidol; pimozide; clozapine; calmidazolin; and, mixtures and pharmaceutically acceptable salts of any of the foregoing. Of the two groups of analgesia-enhancers, the nontoxic NMDA receptor antagonists are preferred and of these, dextromethorphan is preferred for the reasons previously stated.
With regard to dosage levels, 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. Given the wide variations in dosage level of the cyclooxygenase-2 inhibitor which depends to a large extent on the specific cyclooxygenase-2 inhibitor being administered, there can similarly be a wide variation in the dosage level of the nontoxic NMDA receptor antagonist or substance that blocks a major intracellular consequence of NMDA receptor activation. These amounts can be determined for a particular drug combination in accordance with this invention employing routine experimental testing.
While the 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., orally, rectally, parenterally, topically, or by intravenous, intramuscular, intrastemal or subcutaneous injection or in a form suitable by inhalation. The 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.
An analgesic 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. Thus, 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.
For topical administration in the mouth, the analgesic compositions can take the form of buccal or sublingual tablet, drops or lozenges formulated in conventional manner.
For topical administration to the epidermis the compounds of the invention can be formulated as creams, gels, ointments or lotions or as transdermal patches. Such compositions can, 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 can also be formulated as depot preparations. Such long acting formulations can be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds can 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 can be formulated for parenteral administration by injection, conveniently intravenous, intramuscular or subcutaneous injection, for example by bolus injection or continuous intravenous infusion. Formulations for injection can be presented in unit dosage from e.g. in ampoules or in multi-dose containers, with an added preservative. The compositions can take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Alternatively, 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 can 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.
For intranasal administration, the compounds of the invention can be used, for example, as a liquid spray, as a powder or in the form of drops. For administration by inhalation, 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. In the case of a pressurized aerosol the dosage unit can be determined by providing a valve to deliver a metered amount. Capsules and cartridges of e.g. gelatin for use in an inhaler or insulator can be formulated containing a powder mix of a compound of the invention and a suitable powder base such as lactose or starch.
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 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. In addition to the cyclooxygenase-2 inhibitor and nontoxic NMDA receptor antagonist and/or substance that blocks a major intracellular consequence of NMDA receptor activation, 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 can be administrered with the cylooxygenase-2 inhibitor and nontoxic NMDA receptor antagonist and/or substance that blocks a major intracellular consequence of NMDA receptor activation.
EXAMPLES 1-35 The following unit dosage forms are illustrative of the pain-alleviating drug combinations in accordance with the present invention:
Nontoxic
NMDA Receptor Additional Active
Example Cvclooxygenase-2 Inhibitor (mg) Blocker (mg) Component (mg)
1 5-(4-fluorophenyl)-6-r4-(methyl- dextromethorphan sulfonyl)phenyl]spiro[2.4]hept-5-ene (25) hydrobromide (30)
2 5-(4-fluorophenyl)-6-[4-(rnethyl- dextromethorphan acetaminophen (325) sulfonyl)phenyl ]spiro[2.4 ]hept-5-ene (25) hydrobromide (30)
3 5-(4-fluorophenyl)-6-[4-(methyl- dextrorphan sulfonyl)phenyl]spiro[2.4]hept-5-ene (25) hydrobromide (30)
4 5-methanesulfonamido-6- dextromethorphan (2-thienylthio)- 1 -indanone(25) hydrobromide (30)
5 5-methanesulfonamido-6- dextromethorphan acetaminophen (325) (2-thienylthio)-l -indanone(25) hydrobromide (30)
6 5-methanesulfonamido-6- dextrorphan (2-thienylthio)- 1 -indanone(25) hydrobromide (30)
7 5-methanesulfonamido-6- amantadine (30) (2-thienylthio)- 1 -indanone(25)
8 5-methanesulfonamido-6- memantine (30) (2-thienylthio)- 1 -indanone(25)
9 methyl 3,5-bis(l,l-dimethylethyl) dextromethorphan benzoate (25) hydrobromide (30)
10 methyl 3,5-bis(l,l-dimethylethyl) dextromethorphan acetaminophen (325) benzoate (25) hydrobromide (30)
11 methyl 3 ,5-bis( 1 , 1 -dimethylethyl) dextrorphan benzoate (25) hydrobromide (30)
12 methyl 3 ,5-bis( 1 , 1 -dimethylethyl) amantadine (30) benzoate (25)
13 methyl 3,5-bis(l ,l-dimethylethyl) memantine (30) benzoate (25) Nontoxic
NMDA Receptor Additional Active
Example Cvclooxygenase-2 Inhibitor (me) Blocker (mg) Component (mg)
14 l-(2,4,6-trichlorobenzoyl)-5- dextromethorphan methoxy-2-methyl-3-indolyl acetic acid (25) hydrobromide (30)
15 l-(2,4,6-trichlorobenzoyl)-5- dextromethorphan ibuprofen (325) methoxy-2-methyl-3-indolyl acetic acid (25) hydrobromide (30)
16 l-(2,4,6-trichlorobenzoyl)-5- dextrorphan methoxy-2-methyl-3-indolyl acetic acid (25) hydrobromide (30)
17 l-(2,4,6-trichlorobenzoyl)-5- amantadine (30) methoxy-2-methyl-3-indolyl acetic acid (25)
18 l-(2,4,6-trichlorobenzoyl)-5- memantine (30) methoxy-2-methyl-3-indolyl acetic acid (25)
19 3-(4-(aminosulfonyl)phenyl)-2- dextromethorphan (4-fluorophenyl)thiophene (30) hydrobromide (30)
20 3-(4-(aminosulfonyl)phenyl)-2- dextromethorphan aspirin (325) (4-fluorophenyl)thiophene (30) hydrobromide (30)
21 3-(4-(arninosulfonyl)phenyl)-2- dextrorphan (4-fluorophenyl)thiophene (30) hydrobromide (30)
22 3-(4-(aminosulfonyl)phenyl)-2- amantadine (30) (4-fluorophenyl)thiophene (30)
23 3-(4-(aminosulfonyl)phenyl)-2- memantine (30) (4-fluorophenyl)thiophene (30)
24 3,5-bis(l,l-dimethylethyl)benzenethiol (25) dextromethorphan hydrobromide (30)
25 3,5-bis(l,l-dimethylethyl)benzenethiol (25) dextromethorphan acetaminophen (325) hydrobromide (30)
26 3 ,5-bis( 1 , 1 -dimethylethyl)benzenethiol (25) dextrorphan hydrobromide (30)
27 3,5-bis(l,l-dimethylethyl)benzenethiol (25) amantadine (30)
28 3,5-bis(l,l-dimethylethyl)benzenethiol (25) memantine (30)
29 3-(4-(methylsulfonyl)phenyl)-2-phenylbenzo dextromethorphan [bjruran (25) hydrobromide (30) Nontoxic
NMDA Receptor Additional Active
Example Cvclooxvgenase-2 Inhibitor (mg) Blocker (mg) Component (mg)
30 3-(4-(methylsulfonyl)phenyl)-2-phenylbenzo dextromethorphan ibuprofen (325)
[bjfuran (25) hydrobromide (30)
31 3-(4-(methylsulfonyl)phenyl)-2-phenylbenzo dextrorphan
[b]furan (25) hydrobromide (30)
32 4-[l,4-dihydro-3-(trifluoromethyl)-[l] dextromethorphan benzopyrano[4,3-c]pyrazol- 1 -yl] hydrobromide (30) benzenesulfonamide (25)
33 5-(4-(methylsulfonyl)phenyl)-6-phenylimidazo dextromethorphan
[2,l-b]thiazol (25) hydrobromide (30)
34 4-[ 1 ,5-dihydro-6-fluoro-7-methoxy-3- dextromethorphan
(trifluoromethyl)-[2]benzothiopyrano[4,3-c] hydrobromide (30) pyrazol-l-yl]benzenesulfonamide (25)
35 1 -methylsulfonyl-4-[ 1 , 1 -dimethyl-4- dextromethorphan
(4-fluorophenyl)cyclopenta-2,4-diene-3-yl] hydrobromide (30) benzene (25)
In each of these dosage units, the nontoxic NMDA receptor antagonist dextromethorphan hydrobromide significantly potentiates the pain-alleviating activity of the cyclooxygenase-2 inhibitor.

Claims

WHAT IS CLAIMED IS:
1. A method of alleviating a pain state not associated with a cough condition which comprises administering to a mammal exhibiting a pain state not associated with a cough condition (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.
2. The method of Claim 1 wherein the cyclooxygenase-2 inhibitor is selected from the group consisting of substituted spiro compound, sulfonamide, 2,3- substituted cyclopentadienyl compound, aromatic cycloether, 1-aroyl acid, phenyl heterocycle, benzenesulfonamide, cyclic phenolic thioether derivative, 3,4-substituted pyrazole, N-benzyl-3-indoleacetic acid, diaryl bicyclic heterocyclic, benzopyranopyrazolyl derivative, aryl substituted 5,5 fused aromatic nitrogen compound, heteroarylpyranopyrazolyl derivative, pyridyl substituted cyclopentadiene, substituted pyrazole, lactone, ortho substituted phenyl compound, 3,4-diaryl substituted pyridine, N-benzylindol-3-yl propanoic acid derivatives, 5- methanesulfonamido-1-indanones, N-benzylindol-3-yl butanoic acid derivatives, diphenyl-1 ,2-3-thiadiazoles, diaryl-5-oxygenated-2-(5H)-furanones, 3,4-diaryl-2- hydroxy-2,5-dihydrofuranes, diphenyl stilbenes, bisaryl cyclobutene derivatives and MK-966.
3. The method of Claim 2 wherein the substituted spiro compound is selected from the group consisting of 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 and 6-(4-fluorophenyl)-7-[4-(methylsulfonyl)phenyl] spiro[3.4]oct-6-ene, sulfonamides is selected form the group consisting of 5- methanesulfonamido-6-(2-thienylthio)- 1 -indanone and 5-methanesulfonamido-6-(2-(4- methyl-l,3-diazinylthio))-l-indanone, 5-methanesulfonamido-6-(2-thiazolylthio)-l- indanone, the 2,3-substituted cyclopentadienyl compound is selected from the group consisting of l-methylsulfonyl-4-[l , l-dimethyl-4-(4-fluorophenyl)cyclopenta-2,4-dien- 3-yl]benzene, 4-[4-(4-fluorophenyl)-l , l-dimethylcyclopenta-2,4-dien-3- yl]benzenesulfonamide and 1 -methylsulfonyl-4- {4-(4-trifluoromethylphenyl)- 1 - trifluoromethylcyclopenta-2,4-dien-3-yl]benzene, the aromatic cycloether is selected from the group consisting of methyl 3,5-bis(l,l-dimethylethyl)benzoate, 3,5-bis(l,l- dimethylethyl) benzenemethanol and l ,3-bis(l,l-dimethylethyl)-5-(2- chloroethyl)benzene, the 1-aroyl acid is selected from the group consisting of l-(2,4,6- trichlorobenzoyl)-5-methoxy-2-methyl-3-indolyl acetic acid and l-(2,6- dichlorobenzoyl)-5-methoxy-2-methyl-3-indolyl acetic acid, the phenyl heterocycle is selected from the group consisting of 3-(4-(aminosulfonyl)phenyl)-2-(4- fluorophenyl)thiophene, 2-(4-fluorophenyl)-3-(4-(methylsulfonyl)phenyl)-2- cyclopentenone, 4-(4-methylsulfonyl)phenyl)-5-(4-fluorophenyl)isothiazole, 4- (aminosulfonyl)phenyl)-2-(4-fluorophenyl)thiophene, 3-(4-(aminosulfonyl)phenyl)-2-(4- fluorophenyl)-5-(2-propyl)thiophene, 3-(4-(aminosulfonyl)phenyl)-2- cyclohexylthiophene, 3-(4-(aminosulfonyl)phenyl)-2-4-(fluorophenyl)-5-(2-hydroxy-2- propyl)thiophene and 3-(4-(aminosulfonyl)phenyl)-2-(4-fluorophenyl)thiophene, the benzenesulfonamide which is 4-(5-(4-methylphenyl)-3-(trifluoromethyl)-lH-pyrazol-l- yl)benzenesulfonamide, the cyclic phenolic thioether derivative is selected from the group consisting of 3,5-bis(l,l-dimethylethyl)benzenethiol, trans-2-[[3,5-bis(l,l- dimethylethyl)henyl] hiojcyclohexanol and 3,6-dioxabicyclo-[3.1.0]hexane, the 3,4- substituted pyrazole is selected from the group consisting of 4-(4-fluorophenyl)-l- methyl-3-[4-(methylsulfonyl)phenyl]-5-trifluoromethyl)pyrazole, l-benzyl-4-(4- fluorophenyl)-3-[4-(methylsulfonyl)phenyl] -5-(trifluoromethyl)pyrazole and 1 -allyl-4(4- fluorophenyl)-3-[4-methylsulfonyl)phenyl]-5-(trifluoromethyl)-lH-pyrazole, the N- benzyl-3-indoleacetic acid is selected from the group consisting of 2-(5-bromo-l-(4- bromoberizyl)-2-memyl-lH-indol-3-yl)propionic acid, (S)-( +)-2-(5-bromo-l-(4- bromophenyl)-2-methyl-lH-indol-3-yl)acetyl acid and (R)-(-)-2-(5-bromo-l-(4- bromobenzyl)-2-methyl-lH-indol-3-yl)propionic acid, the diaryl bicyclic heterocyclic is selected from the group consisting of 3-(4-(methylsulfonyl)phenyl)-2- phenylbenzo[b]furan, 3-(4-(methanesulfonyl)phenyl)-2-phenylbenzo[b]thiophene and 2- (4-fluorophenyl)-3-(4-aminosulfonyl)phenyl)-4H-thieno[2,3-c]furan-6-one, the benzopyranopyrazolyl derivative is selected from the group consisting of 4-[l,4- dihydro-3-(trifluoromethyl)-[l]benzopyrano[4,3-c]pyrazol-l-yl]benzenesulfonamide, methy 1 [ 1 - [4-(aminosulfonyl)phenyl] - 1 ,4-dihydro-[ 1 ]benzopyrano[4 ,3-c]pyrazol-3-yl] carboxylate and 4-[3-(trifluoromethyl)-lH-benzofuro[3,2-c]pyrazoI-l-yl] benzenesulfonamide, the aryl substituted 5,5 fused aromatic nitrogen compound is selected from the group consisting of 5-(4-methylsulfonyl)phenyl)-6- phenylimidazo[2, 1 -bjthiazole, 2-methyl-5-(methylsulfonyl)phenyl)-6- phenylimidazo[2,l-b]thiazole and 3-methyl-5-(4-methylsulfonyl)phenyl)-6- phenylimidazo[2,l -bjthiazole, the heteroarylpyranopyrazolyl derivative is selected from the group consisting of 4-[l,5-dihydro-6-fluoro-7-methoxy-3-(trifluoromethyl)- [2]benzothiopyrano[4,3-c]pyrazol, 4-[l ,4-dihydro-3-(trifluoromethyl)-[l]benzopyrano- [4,3-c]pyrazol-l-yl]benzenesulfonamide and 1 ,5-dihydro-6-fluoro-7-methoxy-l-[(4- methylsulfonyl)phenyl]-3-(trifluoromethyl)-[2]benzothiopyrano-[4,3-c]pyrazol-l- yljbenzenesulfonamide, the pyridyl substituted cyclopentadienes is selected from the group consisting of l-methylsulfonyl-4-[l ,l-dimethyl-4-(4-fluorophenyl)cyclopenta- 2,4-dien-3-yl]benzene and 4-[4-(4-fluoropyhenyl)-l ,l-dimethylcyclopenta-2,4-dien-3- yljbenzenesulfonamide, the substituted pyrazole is selected from the group consisting of l-ethyl-4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)-lH- pyrazole, 3-amino-4,4,4-trifluoro-2(4-fluorophenyl)-l-[4-(methylthio)phenyl]-2-buten- 1-one and l-benzyl-4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5- (trifluorornethyl)pyrazole, the lactone is selected from the group consisting of 3- phenyl-4-(4-methylsulfonyl)phenyl-2-(5H)-furanone and 3-(3 ,4-difluorophenyl)-4-(4- methylsulfonyl)phenyl)-2-(5H)-furanone, the ortho substituted phenyl compound is selected from the group consisting of 2-[(4-methylthio)phenyl]-l-biphenyl,l- cyclohexene-2-(4'-methylsulfonylphenyl) benzene, and 3-(4'-methylsulfonylphenyl)-4- phenylphenol, the 3,4-diaryl substituted pyridine is selected from the group consisting of 5-(4-fluorophenyl)-2-methoxy-4-[4-(methylsulfonyl)phenyl]-6- (trifluoromethyl)pyridine, 2-ethoxy-5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-6- (trifluoromethyl)pyridine and 5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-2-(2- propynyloxy)-6-(trifluoromethyl)pyridine, the N-benzylindol-3-yl propanoic acid derivatives selected from the group consisting of 3-[l-(p-Bromobenzyl)-5-methoxy-2- methylindol-3-yl]propanoic acid, 3-[l-(p-Bromobenzyl)-5-methoxy-2-methylindol-3- yl]-2,2-dimethyl-propanoic acid and 2-Benzyl-3-[l-(p-Bromobenzyl)-5-methoxy-2- methylindol-3-yl]propanoic acid, the 5-methanesulfonamido-l-indanones selected from the group consisting of 4-(2,4-Dichlorophenoxy)-3-nitrobenzaldehyde and 5- methanesulfonamido-6-(2,4-difluorophenylthio)-l-indanone, the N-benzylindol-3-yl butanoic acid derivatives selected from the group consisting of [4-(l-(4- Bromobenzyl)-5-methoxy-2-methyl-l-H-indol-3-yl)-3-(ethane-l,2-diyl)]butanoic acid and 4-(l-(4-Bromobenzyl)-5-methoxy-2-methyl-l-H-indol-3-yl)-2-methylbutanoic acid, the diphenyl- 1 ,2-3-thiadiazoles selected from the group consisting of 4-Phenyl-5-(4- (methylsulfonyl)-phenyl-l ,2,3-thiadiazole, 4-(4-fluorophenyl)-5-(4- (methylsulfonyl)phenyl-l ,2,3-thiadiazole and 4-(3-fluorophenyl)-5-(4- (methylsulfonyl)phenyl-l ,2,3-thiadiazole, the diaryl-5-oxygenated-2-(5H)-furanones selected from the group consisting of 5-hydroxy-3-(3,4-difluorophenyl)-4-(4- (methylsulfonyl)phenyl)-2-(5H)-furanone, 5-hydroxy-5-methyl-,4-(4- (methylsulfonyl)phenyl)-3-phenyl-2-(5H)-furanone and 5-hydroxy-4-(4- (methylsulfonyl)phenyl)-3-phenyl-2-(5H)-furanone, the 3,4-diaryl-2-hydroxy-2,5- dihydrofuranes selected from the group consisting of 3-(3,5-difluorophenyl)-5,5- dimethyl-2-hydroxy-4-(4-(methylsulfonyl)phenyl)-2,5-dihydrofuran, 5,5-dimethyl-3-(4- fluorophenyl)-2-hydroxy-4-(4-(methylsulfonyl)phenyl)-2,5-dihydrofuran and 5,5- dimethyl-2-ethoxy-3-(3-fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2,5-dihydrofuran, the diphenyl stilbenes selected from the group consisting of (E)-3-(4- methylsulfonyl)phenyl-2-phenylbut-2-enoic acid methyl ester, (E)-3- (methylsulfonyl)phenyl-2-phenylbut-2-enoic acid and (E)-3-(4-methylsulfonyl)phenyl-l- morpholin-4-yl-2-phenylbut-2en-l-one, the alkylated styrenes selected from the group consisting of 2-(3-fluorophenyl)-4-methyl-3-(4-(methylsulfonyl)-phenyl)-2-(Z)-penten- 1.4-diol, acetic acid 4-acetoxy-2-(3-fluorophenyl)-4-methyl-3-(4-
(methylsulfonyl)phenyl)-2-(Z)-pent-2-enyl ester and 2-(3-fluorophenyl)-4-methoxy-4- methyl-3-((4-methylsulfonyllphenyl)-2-(Z)-pentenoic acid, and the bisaryl cyclobutene derivatives selected from the group consisting of 4,4-dichloro-3-(4-methylthiophenyl)- 2-phenyl-2-cyclobuten-l-one, 4,4-dichloro-3-(4-methylsulfonylphenyl)-2-phenyl-2- cyclobuten-1-one and 4-chloro-3-(4-methylsulfonylphenyl)-2-phenyl-2-cyclobuten-l- one.
4. The method of Claim 1 containing a therapeutically effective amount of at least one other pharmacologically active substance (c).
5. The method of Claim 4 wherein the pharmacologically active substance (c) is selected from the group consisting of non-narcotic analgesics and narcotic analgesics.
6. The method of Claim 5 wherein the non-narcotic analgesic is selected from the group consisting of 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 and zomepirac.
7. The method of Claim 5 wherein the narcotic analgesic is selected from the group consisting of codeine, dihydrocodeine, hydrocodone, levorphanol, morphine and oxycodone.
8. The method of Claim 1 wherein the nontoxic N-methyl-D- aspartate receptor antagonist is at least one member selected from the group consisting of dextromethorphan, dextrorphan, amantadine, memantine and pharmaceutically acceptable salts thereof.
9. The method of Claim 3 wherein the nontoxic N-methyl-D- aspartate receptor antagonist is at least one member selected from the group consisting of dextromethorphan, dextrorphan, amantadine, memantine and pharmaceutically acceptable salts thereof.
10. The method of Claim 1 wherein (a) and (b) are coadministered.
11. The method of Claim 8 wherein (a) and (b) are coadministered as a sustained release dosage form.
12. The method of Claim 1 wherein the pain being treated or to be treated is chronic pain, post-operative pain, lumbosacral pain, musculo-skeletal pain, headache or migraine.
13. The method of Claim 8 wherein the pain being treated or to be treated is chronic pain, post-operative pain, lumbosacral pain, musculo-skeletal pain, headache or migraine.
PCT/US1998/024317 1998-11-12 1998-11-12 Cox-2 inhibitors in combination with nmda-blockers for treating pain WO2000029023A1 (en)

Priority Applications (5)

Application Number Priority Date Filing Date Title
AU14086/99A AU1408699A (en) 1998-11-12 1998-11-12 Cox-2 inhibitors in combination with nmda-blockers for treating pain
EP98957950A EP1146905A1 (en) 1998-11-12 1998-11-12 Cox-2 inhibitors in combination with nmda-blockers for treating pain
JP2000582069A JP2002538078A (en) 1998-11-12 1998-11-12 COX-2 inhibitor combined with NMDA-blocker to treat pain
PCT/US1998/024317 WO2000029023A1 (en) 1998-11-12 1998-11-12 Cox-2 inhibitors in combination with nmda-blockers for treating pain
CA002351224A CA2351224A1 (en) 1998-11-12 1998-11-12 Cox-2 inhibitors in combination with nmda-blockers for treating pain

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US1998/024317 WO2000029023A1 (en) 1998-11-12 1998-11-12 Cox-2 inhibitors in combination with nmda-blockers for treating pain

Publications (1)

Publication Number Publication Date
WO2000029023A1 true WO2000029023A1 (en) 2000-05-25

Family

ID=22268299

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1998/024317 WO2000029023A1 (en) 1998-11-12 1998-11-12 Cox-2 inhibitors in combination with nmda-blockers for treating pain

Country Status (5)

Country Link
EP (1) EP1146905A1 (en)
JP (1) JP2002538078A (en)
AU (1) AU1408699A (en)
CA (1) CA2351224A1 (en)
WO (1) WO2000029023A1 (en)

Cited By (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10059020A1 (en) * 2000-11-28 2002-05-29 Gruenenthal Gmbh Dosage forms that can be administered parenterally
WO2004039371A2 (en) * 2002-10-29 2004-05-13 Pharmacia Corporation Compositions of cyclooxygenase-2 selective inhibitors and nmda receptor antagonists for the treatment or prevention of neuropathic pain
WO2006024018A2 (en) * 2004-08-24 2006-03-02 Neuromolecular Pharmaceuticals, Inc. Compositions for treating nociceptive pain
WO2008055945A1 (en) 2006-11-09 2008-05-15 Probiodrug Ag 3-hydr0xy-1,5-dihydr0-pyrr0l-2-one derivatives as inhibitors of glutaminyl cyclase for the treatment of ulcer, cancer and other diseases
WO2008065141A1 (en) 2006-11-30 2008-06-05 Probiodrug Ag Novel inhibitors of glutaminyl cyclase
WO2008104580A1 (en) 2007-03-01 2008-09-04 Probiodrug Ag New use of glutaminyl cyclase inhibitors
US7732162B2 (en) 2003-05-05 2010-06-08 Probiodrug Ag Inhibitors of glutaminyl cyclase for treating neurodegenerative diseases
WO2011029920A1 (en) 2009-09-11 2011-03-17 Probiodrug Ag Heterocylcic derivatives as inhibitors of glutaminyl cyclase
WO2011107530A2 (en) 2010-03-03 2011-09-09 Probiodrug Ag Novel inhibitors
WO2011110613A1 (en) 2010-03-10 2011-09-15 Probiodrug Ag Heterocyclic inhibitors of glutaminyl cyclase (qc, ec 2.3.2.5)
WO2011131748A2 (en) 2010-04-21 2011-10-27 Probiodrug Ag Novel inhibitors
WO2012123563A1 (en) 2011-03-16 2012-09-20 Probiodrug Ag Benz imidazole derivatives as inhibitors of 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
US20130274282A1 (en) * 2012-04-16 2013-10-17 Herriot Tabuteau Compositions and methods comprising celecoxib or related compounds and dextromethorphan
US8834924B2 (en) 2004-06-17 2014-09-16 Forest Laboratories Holdings Limited Immediate release formulations of 1-aminocyclohexane compounds, memantine and neramexane
EP2865670A1 (en) 2007-04-18 2015-04-29 Probiodrug AG Thiourea derivatives as glutaminyl cyclase inhibitors
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 (en) 2017-09-29 2019-04-03 Probiodrug AG Inhibitors of glutaminyl cyclase
US10959958B2 (en) 2014-10-20 2021-03-30 Pharmaceutical Manufacturing Research Services, Inc. Extended release abuse deterrent liquid fill dosage form

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BRPI0412684A (en) * 2003-07-17 2006-10-03 Plexxinko Inc par active compounds

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5409944A (en) * 1993-03-12 1995-04-25 Merck Frosst Canada, Inc. Alkanesulfonamido-1-indanone derivatives as inhibitors of cyclooxygenase
WO1996007412A1 (en) * 1994-09-02 1996-03-14 Virginia Commonwealth University Composition alleviating pain, containing a non-narcotic analgesic and an analgesia enhancer
US5521213A (en) * 1994-08-29 1996-05-28 Merck Frosst Canada, Inc. Diaryl bicyclic heterocycles as inhibitors of cyclooxygenase-2
WO1998050075A1 (en) * 1997-05-07 1998-11-12 Algos Pharmaceutical Corporation Cox-2 inhibitors in combination with nmda-blockers for treating pain
WO1999025382A1 (en) * 1997-11-18 1999-05-27 Laboratoires Upsa Pharmaceutical combination of a cyclooxygenase-2 inhibitor

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5409944A (en) * 1993-03-12 1995-04-25 Merck Frosst Canada, Inc. Alkanesulfonamido-1-indanone derivatives as inhibitors of cyclooxygenase
US5521213A (en) * 1994-08-29 1996-05-28 Merck Frosst Canada, Inc. Diaryl bicyclic heterocycles as inhibitors of cyclooxygenase-2
WO1996007412A1 (en) * 1994-09-02 1996-03-14 Virginia Commonwealth University Composition alleviating pain, containing a non-narcotic analgesic and an analgesia enhancer
WO1998050075A1 (en) * 1997-05-07 1998-11-12 Algos Pharmaceutical Corporation Cox-2 inhibitors in combination with nmda-blockers for treating pain
WO1999025382A1 (en) * 1997-11-18 1999-05-27 Laboratoires Upsa Pharmaceutical combination of a cyclooxygenase-2 inhibitor

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CASHMAN J N: "The mechanisms of action of NSAIDs in analgesia.", DRUGS, vol. 52, no. Supp 5, 1996, pages 13 - 23, XP002074394 *
PRICE D D ET AL: "EFFECTS OF THE COMBINED ORAL ADMINISTRATION OF NSAIDS AND DEXTROMETHORPHAN ON BEHAVIORAL SYMPTOMS INDICATIVE OF ARTHRITIC PAIN IN RATS", PAIN, vol. 68, no. 1, November 1996 (1996-11-01), pages 119 - 127, XP002061724 *

Cited By (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10059020A1 (en) * 2000-11-28 2002-05-29 Gruenenthal Gmbh Dosage forms that can be administered parenterally
US6875447B2 (en) 2000-11-28 2005-04-05 Grunenthal Gmbh Parenteral dosage forms comprising a suspension of tramadol salt and diclofenac salt
US8309570B2 (en) 2001-06-07 2012-11-13 Analgesic Neuropharmaceuticals, Llc Treatment of central neuropathic pain
WO2004039371A2 (en) * 2002-10-29 2004-05-13 Pharmacia Corporation Compositions of cyclooxygenase-2 selective inhibitors and nmda receptor antagonists for the treatment or prevention of neuropathic pain
WO2004039371A3 (en) * 2002-10-29 2004-06-17 Pharmacia Corp Compositions of cyclooxygenase-2 selective inhibitors and nmda receptor antagonists for the treatment or prevention of neuropathic pain
US7732162B2 (en) 2003-05-05 2010-06-08 Probiodrug Ag Inhibitors of glutaminyl cyclase for treating neurodegenerative diseases
US8809010B2 (en) 2003-05-05 2014-08-19 Probiodrug Ag Method for prophylactic treatment of alzheimer's disease using inhibitors of glutaminyl cyclase and glutamate cyclases
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
US8834924B2 (en) 2004-06-17 2014-09-16 Forest Laboratories Holdings Limited Immediate release formulations of 1-aminocyclohexane compounds, memantine and neramexane
WO2006024018A3 (en) * 2004-08-24 2006-07-20 Neuromolecular Pharmaceuticals Compositions for treating nociceptive pain
WO2006024018A2 (en) * 2004-08-24 2006-03-02 Neuromolecular Pharmaceuticals, Inc. Compositions for treating nociceptive pain
WO2008055945A1 (en) 2006-11-09 2008-05-15 Probiodrug Ag 3-hydr0xy-1,5-dihydr0-pyrr0l-2-one derivatives as inhibitors of glutaminyl cyclase for the treatment of ulcer, cancer and other diseases
WO2008065141A1 (en) 2006-11-30 2008-06-05 Probiodrug Ag Novel inhibitors of glutaminyl cyclase
EP2481408A2 (en) 2007-03-01 2012-08-01 Probiodrug AG New use of glutaminyl cyclase inhibitors
WO2008104580A1 (en) 2007-03-01 2008-09-04 Probiodrug Ag New use of glutaminyl cyclase inhibitors
EP2865670A1 (en) 2007-04-18 2015-04-29 Probiodrug AG Thiourea derivatives as glutaminyl cyclase inhibitors
WO2011029920A1 (en) 2009-09-11 2011-03-17 Probiodrug Ag Heterocylcic derivatives as inhibitors of glutaminyl cyclase
WO2011107530A2 (en) 2010-03-03 2011-09-09 Probiodrug Ag Novel inhibitors
WO2011110613A1 (en) 2010-03-10 2011-09-15 Probiodrug Ag Heterocyclic inhibitors of glutaminyl cyclase (qc, ec 2.3.2.5)
WO2011131748A2 (en) 2010-04-21 2011-10-27 Probiodrug Ag Novel inhibitors
WO2012123563A1 (en) 2011-03-16 2012-09-20 Probiodrug Ag Benz imidazole derivatives as inhibitors of glutaminyl cyclase
US20130274282A1 (en) * 2012-04-16 2013-10-17 Herriot Tabuteau Compositions and methods comprising celecoxib or related compounds and dextromethorphan
US10195153B2 (en) 2013-08-12 2019-02-05 Pharmaceutical Manufacturing Research Services, Inc. Extruded immediate release abuse deterrent pill
US10639281B2 (en) 2013-08-12 2020-05-05 Pharmaceutical Manufacturing Research Services, Inc. Extruded immediate release abuse deterrent pill
US9492444B2 (en) 2013-12-17 2016-11-15 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
US10172797B2 (en) 2013-12-17 2019-01-08 Pharmaceutical Manufacturing Research Services, Inc. Extruded extended release abuse deterrent pill
US10792254B2 (en) 2013-12-17 2020-10-06 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
US10959958B2 (en) 2014-10-20 2021-03-30 Pharmaceutical Manufacturing Research Services, Inc. Extended release abuse deterrent liquid fill dosage form
EP3461819A1 (en) 2017-09-29 2019-04-03 Probiodrug AG Inhibitors of glutaminyl cyclase

Also Published As

Publication number Publication date
EP1146905A1 (en) 2001-10-24
AU1408699A (en) 2000-06-05
CA2351224A1 (en) 2000-05-25
JP2002538078A (en) 2002-11-12

Similar Documents

Publication Publication Date Title
WO2000029023A1 (en) Cox-2 inhibitors in combination with nmda-blockers for treating pain
WO1998050075A1 (en) Cox-2 inhibitors in combination with nmda-blockers for treating pain
AU760735B2 (en) A method for treating inflammatory diseases by administering a thrombin inhibitor
EP0942752B1 (en) Anticonvulsant containing composition for treating neuropathic pain
US6136804A (en) Combination therapy for treating, preventing, or reducing the risks associated with acute coronary ischemic syndrome and related conditions
AU745797B2 (en) Method of using cyclooxygenase-2 inhibitors in the prevention of cardiovascular disorders
US20030212138A1 (en) Combinations of peroxisome proliferator-activated receptor-alpha agonists and cyclooxygenase-2 selective inhibitors and therapeutic uses therefor
EP1465621A2 (en) Compositions and methods of treatment involving peroxisome proliferator activated receptor gamma agonists and cyclooxygenase 2 selective inhibitors
WO1998015275A2 (en) Method and potentiated composition for treating migraine
EP1283723A2 (en) Combination therapy using cox-2 selective inhibitor and thromboxane inhibitor and compositions therefor
WO2000029022A1 (en) Cox-2 inhibitors in combination with centrally acting analgesics
JP2002505306A (en) Combination of selective NMMANR2B antagonist and COX-2 inhibitor
JP2005501850A (en) A composition for treating and preventing pain and inflammation comprising a cyclooxygenase-2 selective inhibitor and chondroitin sulfate
US20020035156A1 (en) Combination therapy in the prevention of cardiovascular disorders
WO1999045913A1 (en) Combination therapy and composition for acute coronary ischemic syndrome and related conditions
US20070072861A1 (en) Method of using cyclooxygenase-2 inhibitors in the prevention of cardiovascular disorders
US20030207846A1 (en) Treatment of pain, inflammation, and inflammation-related disorders with a combination of a cyclooxygenase-2 selective inhibitor and aspirin
WO2005020926A2 (en) Treatment or prevention of vascular disorders with cox-2 inhibitors in combination with cyclic amp-specific phosphodiesterase inhibitors
PL206268B1 (en) Analgesic and anti-inflammatory compositions containing cox-2 inhibitors
CZ9903642A3 (en) Use of cyclooxygenase-2 inhibitors for prevention of cardiovascular diseases

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GD GE GH GM HR HU ID IL IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG US UZ VN YU ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW SD SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
ENP Entry into the national phase

Ref document number: 2351224

Country of ref document: CA

Ref country code: CA

Ref document number: 2351224

Kind code of ref document: A

Format of ref document f/p: F

ENP Entry into the national phase

Ref country code: JP

Ref document number: 2000 582069

Kind code of ref document: A

Format of ref document f/p: F

WWE Wipo information: entry into national phase

Ref document number: 14086/99

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 512002

Country of ref document: NZ

WWE Wipo information: entry into national phase

Ref document number: 1998957950

Country of ref document: EP

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

WWP Wipo information: published in national office

Ref document number: 1998957950

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 09868816

Country of ref document: US

WWW Wipo information: withdrawn in national office

Ref document number: 1998957950

Country of ref document: EP

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载