WO2011077313A1 - Pipéridinecarboxamides en tant qu'inhibiteurs de mpges - 1 - Google Patents

Pipéridinecarboxamides en tant qu'inhibiteurs de mpges - 1 Download PDF

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Publication number
WO2011077313A1
WO2011077313A1 PCT/IB2010/055736 IB2010055736W WO2011077313A1 WO 2011077313 A1 WO2011077313 A1 WO 2011077313A1 IB 2010055736 W IB2010055736 W IB 2010055736W WO 2011077313 A1 WO2011077313 A1 WO 2011077313A1
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Prior art keywords
pain
formula
compound
mpges
compounds
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PCT/IB2010/055736
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English (en)
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John Robert Springer
Michael Lawrence Vazquez
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Pfizer Inc.
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Publication of WO2011077313A1 publication Critical patent/WO2011077313A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the invention relates to piperidinecarboxamides, to their use in medicine, to compositions containing them, to processes for their preparation and to intermediates used in such processes.
  • PGE2 prostaglandin E2
  • Prostaglandin synthase (PGHS) or more commonly cyclooxygenase (COX) is the enzyme that mediates biosynthesis of prostaglandins (PGs) and thromboxane (TxA2) from arachidonic acid, and whose inhibition underlies the effectiveness of a variety of anti-inflammatory drugs.
  • COX activity originates from two distinct and independently regulated isozymes, COX-1 and COX-2.
  • COX-2 is inducible and is the major source of PGE2 which mediates pain and inflammation, while COX-1 catalyzes the formation of PGs that serve housekeeping functions, such as the maintenance of gastrointestinal (Gl) integrity.
  • Non-steroidal anti-inflammatory drugs (NSAIDs) are non-selective and inhibit both COX- 1 and COX-2, whereas coxibs are selective for COX-2.
  • NSAIDs non-selective and inhibit both COX- 1 and COX-2
  • coxibs are selective for COX-2.
  • a few coxibs have been shown in controlled trials to reduce the incidence of serious gastrointestinal (Gl) adverse effects when compared with traditional NSAIDs.
  • microsomal prostaglandin E synthase type 1 (mPGES-1 ) occurs immediately downstream of COX-2 in the PGE2 pathway. It has recently been found to be up-regulated in response to inflammatory signals and is primarily responsible for the generation of PGE2 during inflammation. As PGE2 has been shown to be involved in arthritis and inflammation, mPGES-1 has been suggested as a new drug target.
  • mPGES-1 is a member of the Membrane Associated Proteins in Eicosanoid and Glutathione metabolism (MAPEG) family of glutathione transferases, which also includes FLAP and LTC4 synthase.
  • Murine knockouts of mPGES-1 demonstrate almost complete reduction of PGE2 from peritoneal macrophages stimulated with lipopolysaccharide (LPS) and complete reversal of the severity and incidence in collagen induced arthritis (Trebino, C. et al. PNAS USA 2003, 100(15), 9044). Therefore, a selective inhibitor of mPGES-1 would be expected to inhibit PGE2 production induced by inflammation, while sparing constitutive PGE2, prostacyclin (PGI2) and thromboxane (TxA2) production.
  • MAPEG Eicosanoid and Glutathione metabolism
  • Inhibitors of mPGES-1 would also inhibit the production of PGE2 from COX-2, but not PGI2 or PGs derived from COX-1 thereby avoiding Gl effects.
  • PGI2 is formed by prostacyclin synthase (PGIS) acting on the PGH2 formed by COX and is the major product of arachidonic acid in vascular endothelial cells. PGI2 inhibits platelet aggregation, vascular smooth muscle contraction and proliferation, leukocyte- endothelial cell interactions and cholesteryl ester hydrolase. It also activates reverse cholesterol transport.
  • PGIS prostacyclin synthase
  • TxA2 thromboxane A2
  • mPGES-1 functions downstream of COX-2, selective inhibition of mPGES- 1 does not interfere with the production of PGH2 and thus levels of PGI2, PGD2 and TxA2 are also not inhibited. Accordingly, mPGES-1 inhibition has the potential to relieve pain and inflammation while minimizing any unwanted Gl or CV adverse effects.
  • Certain mPGES-1 inhibitors are known.
  • WO2009/098282 discloses certain thiophene derivatives said to be useful in the treatment of pain and inflammation.
  • WO2008/084218 discloses certain benzazole derivatives also said to be useful in the treatment inflammation and inflammatory pain.
  • WO2008/006663 discloses certain arylindole derivatives said to be useful in the treatment of a number of inflammatory processes and pain.
  • the ideal drug candidate will have good aqueous solubility and exist in a physical form that is stable, non-hygroscopic and easily formulated.
  • references to compounds of the invention include the compound of formula (I) or pharmaceutically acceptable salt, solvate, or multi-component complex thereof, or pharmaceutically acceptable solvate or multi-component complex of a pharmaceutically acceptable salt of the compound of formula (I), as discussed in more detail below.
  • Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate,
  • hexafluorophosphate hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinofoate salts.
  • Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.
  • Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts.
  • salts include ones wherein the counterion is optically active, for example d-lactate or l-lysine, or racemic, for example dl-tartrate or dl-arginine.
  • compositions of the compound of formula (I) may be prepared by one or more of three methods:
  • the resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent.
  • the degree of ionisation in the resulting salt may vary from completely ionised to almost non-ionised.
  • the compound of formula (I) or pharmaceutically acceptable salts thereof may exist in both unsolvated and solvated forms.
  • the term 'solvate' is used herein to describe a molecular complex comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable solvent molecules, for example, ethanol.
  • the term 'hydrate' is employed when said solvent is water.
  • Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D 2 0, d6- acetone and d 6 -DMSO.
  • a currently accepted classification system for organic hydrates is one that defines isolated site, channel, or metal-ion coordinated hydrates - see Polymorphism in
  • Isolated site hydrates are ones in which the water molecules are isolated from direct contact with each other by intervening organic molecules. In channel hydrates, the water molecules lie in lattice channels where they are next to other water molecules. In metal-ion coordinated hydrates, the water molecules are bonded to the metal ion.
  • the complex When the solvent or water is tightly bound, the complex will have a well-defined stoichiometry independent of humidity. When, however, the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, the water/solvent content will be dependent on humidity and drying conditions. In such cases, non-stoichiometry will be the norm.
  • the compounds of the invention may exist in a continuum of solid states ranging from fully amorphous to fully crystalline.
  • the term 'amorphous' refers to a state in which the material lacks long range order at the molecular level and, depending upon temperature, may exhibit the physical properties of a solid or a liquid. Typically such materials do not give distinctive X-ray diffraction patterns and, while exhibiting the properties of a solid, are more formally described as a liquid.
  • a change from solid to liquid properties occurs which is characterised by a change of state, typically second order ('glass transition').
  • 'crystalline' refers to a solid phase in which the material has a regular ordered internal structure at the molecular level and gives a distinctive X-ray diffraction pattern with defined peaks. Such materials when heated sufficiently will also exhibit the properties of a liquid, but the change from solid to liquid is characterised by a phase change, typically first order ('melting point').
  • multi-component complexes other than salts and solvates of the compound of formula (I) or pharmaceutically acceptable salts thereof wherein the drug and at least one other component are present in stoichiometric or non-stoichiometric amounts.
  • Complexes of this type include clathrates (drug-host inclusion complexes) and co-crystals. The latter are typically defined as crystalline complexes of neutral molecular constituents which are bound together through non-covalent interactions, but could also be a complex of a neutral molecule with a salt.
  • Co-crystals may be prepared by melt crystallisation, by
  • the compounds of the invention may also exist in a mesomorphic state
  • mesophase or liquid crystal when subjected to suitable conditions.
  • the mesomorphic state is intermediate between the true crystalline state and the true liquid state (either melt or solution).
  • Mesomorphism arising as the result of a change in temperature is described as 'thermotropic' and that resulting from the addition of a second component, such as water or another solvent, is described as 'lyotropic'.
  • the compounds of the invention may be administered as prodrugs.
  • certain derivatives of the compound of formula (I) which may have little or no pharmacological activity themselves can, when administered into or onto the body, be converted into the compound of formula (I) having the desired activity, for example, by hydrolytic cleavage.
  • Such derivatives are referred to as 'prodrugs'. Further information on the use of prodrugs may be found in 'Pro-drugs as Novel Delivery Systems, Vol. 14, ACS
  • Prodrugs can, for example, be produced by replacing appropriate functionalities present in the compound of formula (I) with certain moieties known to those skilled in the art as 'pro-moieties' as described, for example, in "Design of Prodrugs" by H
  • prodrugs examples include phosphate prodrugs, such as dihydrogen or dialkyl (e.g. di-tert-butyl) phosphate prodrugs. Further examples of replacement groups in accordance with the foregoing examples and examples of other prodrug types may be found in the aforementioned references.
  • metabolites of compounds of formula (I) that is, compounds formed in vivo upon administration of the drug.
  • Some examples of metabolites in accordance with the invention include, where the compound of formula (I) contains a phenyl (Ph) moiety, a phenol derivative thereof (-Ph > -PhOH);
  • a compound of the invention is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
  • enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC).
  • HPLC high pressure liquid chromatography
  • the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of formula (I) contains an acidic or basic moiety, a base or acid such as 1- phenylethylamine or tartaric acid.
  • a suitable optically active compound for example, an alcohol, or, in the case where the compound of formula (I) contains an acidic or basic moiety, a base or acid such as 1- phenylethylamine or tartaric acid.
  • the resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s)
  • Chiral compounds of the invention may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% by volume of isopropanol, typically from 2% to 20%, and from 0 to 5% by volume of an alkylamine, typically 0.1 % diethylamine.
  • chromatography typically HPLC
  • a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% by volume of isopropanol, typically from 2% to 20%, and from 0 to 5% by volume of an alkylamine, typically 0.1 % diethylamine.
  • the scope of the invention includes all crystal forms of the compounds of the invention, including racemates and racemic mixtures (conglomerates) thereof.
  • Stereoisomeric conglomerates may also be separated by the conventional techniques described herein just above.
  • the scope of the invention includes all pharmaceutically acceptable isotopically- labelled compounds of the invention wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature.
  • isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2 H and 3 H, carbon, such as 11 C, 13 C and 14 C, chlorine, such as 36 CI, fluorine, such as 18 F, iodine, such as 123 l and 125 l, nitrogen, such as 13 N and 15 N, oxygen, such as 15 0, 17 0 and 18 0, phosphorus, such as 32 P, and sulphur, such as 35 S.
  • isotopically-labelled compounds of the invention for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies.
  • Substitution with heavier isotopes such as deuterium, i.e. 2 H may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
  • Isotopically-labeled compound of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagent in place of the non- labeled reagent previously employed.
  • intermediate compounds as hereinafter defined, all salts, solvates and complexes thereof and all solvates and complexes of salts thereof as defined hereinbefore for the compound of formula (I).
  • the invention includes all polymorphs of the aforementioned species and crystal habits thereof.
  • the compounds of the invention may be prepared by any method known in the art for the preparation of compounds of analogous structure.
  • the compounds of the invention can be prepared by the procedures described by reference to the Schemes that follow, or by the specific methods described in the Examples, or by similar processes to either.
  • the skilled person will appreciate that it may be necessary or desirable at any stage in the synthesis of compounds of the invention to protect one or more sensitive groups, so as to prevent undesirable side reactions.
  • the protecting groups used in the preparation of the compounds of the invention may be used in conventional manner. See, for example, those described in 'Greene's Protective Groups in Organic Synthesis' by Theodora W Greene and Peter G M Wuts, fourth edition, (John Wiley and Sons, 2006), in particular chapter 7 ("Protection for the Amino Group"), incorporated herein by reference, which also describes methods for the removal of such groups.
  • the invention provides a carboxylic acid of formulae (III).
  • crystalline or amorphous products may exist in a continuum of solid states ranging from fully amorphous to fully crystalline. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose.
  • They may be administered alone or in combination with one or more other compounds of the invention or in combination with one or more other drugs (or as any combination thereof). Generally, they will be administered as a formulation in association with one or more pharmaceutically acceptable excipients.
  • the invention provides a pharmaceutical composition comprising a compound of the invention together with one or more pharmaceutically acceptable excipients.
  • compositions suitable for the delivery of compounds of the present invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation may be found, for example, in "Remington's Pharmaceutical Sciences", 19th Edition (Mack Publishing Company, 1995).
  • Suitable modes of administration include oral, parenteral, topical,
  • Formulations suitable for the aforementioned modes of administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • the compounds of the invention may be administered orally.
  • Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth.
  • Formulations suitable for oral administration include solid formulations such as tablets, capsules containing particulates, liquids, or powders, lozenges (including liquid-filled), chews, multi- and nano-particulates, gels, solid solution, liposome, films, ovules, sprays, liquid formulations and
  • buccal/mucoadhesive patches are buccal/mucoadhesive patches.
  • Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be employed as fillers in soft or hard capsules and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet.
  • the compounds of the invention may also be used in fast-dissolving, fast- disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, H (6), 981-986, by Liang and Chen (2001 ).
  • the drug may make up from 1 weight % to 80 weight % of the dosage form, more typically from 5 weight % to 60 weight % of the dosage form.
  • tablets generally contain a disintegrant.
  • disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinised starch and sodium alginate.
  • the disintegrant will comprise from 1 weight % to 25 weight %, preferably from 5 weight % to 20 weight % of the dosage form.
  • Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinised starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.
  • lactose monohydrate, spray-dried monohydrate, anhydrous and the like
  • mannitol xylitol
  • dextrose sucrose
  • sorbitol microcrystalline cellulose
  • starch dibasic calcium phosphate dihydrate
  • Tablets may also optionally comprise surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc.
  • surface active agents such as sodium lauryl sulfate and polysorbate 80
  • glidants such as silicon dioxide and talc.
  • surface active agents may comprise from 0.2 weight % to 5 weight % of the tablet, and glidants may comprise from 0.2 weight % to 1 weight % of the tablet.
  • Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate.
  • Lubricants generally comprise from 0.25 weight % to 10 weight %, preferably from 0.5 weight % to 3 weight % of the tablet.
  • Other possible ingredients include anti-oxidants, colourants, flavouring agents, preservatives and taste- masking agents.
  • Exemplary tablets contain up to about 80% drug, from about 10 weight % to about 90 weight % binder, from about 0 weight % to about 85 weight % diluent, from about 2 weight % to about 10 weight % disintegrant, and from about 0.25 weight % to about 10 weight % lubricant.
  • Tablet blends may be compressed directly or by roller to form tablets. Tablet blends or portions of blends may alternatively be wet-, dry-, or melt- granulated, melt congealed, or extruded before tabletting.
  • the final formulation may comprise one or more layers and may be coated or uncoated; it may even be encapsulated. The formulation of tablets is discussed in "Pharmaceutical Dosage
  • Suitable modified release formulations for the purposes of the invention are described in US Patent No. 6, 106,864. Details of other suitable release technologies such as high energy dispersions and osmotic and coated particles are to be found in "Pharmaceutical Technology On-line", 25(2), 1 -14, by Verma et al (2001 ). The use of chewing gum to achieve controlled release is described in WO 00/35298.
  • the compounds of the invention may also be administered directly into the blood stream, into muscle, or into an internal organ. Suitable means for parenteral
  • administration include intravenous, intraarterial, intraperitoneal, intrathecal,
  • Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.
  • Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.
  • excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9)
  • a suitable vehicle such as sterile, pyrogen-free water.
  • parenteral formulations under sterile conditions may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.
  • solubility of the compound of formula (I) used in the preparation of parenteral solutions may be increased by the use of appropriate formulation techniques, such as the incorporation of solubility-enhancing agents.
  • Formulations for parenteral administration may be formulated to be immediate and/or modified release. Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • compounds of the invention may be formulated as a solid, semi-solid, or thixotropic liquid for administration as an implanted depot providing modified release of the active compound. Examples of such formulations include drug- coated stents and poly(dl-lactic-coglycolic)acid (PGLA) microspheres.
  • PGLA poly(dl-lactic-coglycolic)acid
  • the compounds of the invention may also be administered topically to the skin or mucosa, that is, dermally or transdermally.
  • Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibres, bandages and
  • Liposomes may also be used.
  • Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol.
  • Penetration enhancers may be incorporated - see, for example, J Pharm Sci, 88 (10), 955-958, by Finnin and Morgan (October 1999).
  • Other means of topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis and microneedle or needle-free (e.g.
  • the compounds of the invention can also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurised container, pump, spray, atomiser (preferably an atomiser using electrohydrodynamics to produce a fine mist), or nebuliser, with or without the use of a suitable propellant, such as 1 ,1 , 1 ,2-tetrafluoroethane or 1 ,1 ,1 ,2,3,3,3- heptafluoropropane.
  • the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.
  • the pressurised container, pump, spray, atomizer, or nebuliser contains a solution or suspension of the compound(s) of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilising, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.
  • a solution or suspension of the compound(s) of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilising, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.
  • the drug product Prior to use in a dry powder or suspension formulation, the drug product is micronised to a size suitable for delivery by inhalation (typically less than 5 microns). This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenisation, or spray drying.
  • comminuting method such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenisation, or spray drying.
  • Capsules made, for example, from gelatin or hydroxypropylmethylcellulose
  • blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound of the invention, a suitable powder base such as lactose or starch and a performance modifier such as l-leucine, mannitol, or magnesium stearate.
  • the lactose may be anhydrous or in the form of the monohydrate, preferably the latter.
  • Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.
  • a suitable solution formulation for use in an atomiser using electrohydrodynamics to produce a fine mist may contain from 1 ⁇ g to 20mg of the compound of the invention per actuation and the actuation volume may vary from 1 ⁇ to 100 ⁇ .
  • a typical formulation may comprise a compound of formula (I), propylene glycol, sterile water, ethanol and sodium chloride.
  • Alternative solvents which may be used instead of propylene glycol include glycerol and polyethylene glycol.
  • Suitable flavours such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium, may be added to those formulations of the invention intended for inhaled/intranasal administration.
  • the dosage unit is determined by means of a valve which delivers a metered amount.
  • Units in accordance with the invention are typically arranged to administer a metered dose or "puff' containing from ⁇ g to 100mg of the compound of formula (I).
  • the overall daily dose will typically be in the range ⁇ g to 200mg which may be administered in a single dose or, more usually, as divided doses throughout the day.
  • the compounds of the invention may be administered rectally or vaginally, for example, in the form of a suppository, pessary, microbicide, vaginal ring or enema.
  • Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate.
  • the compounds of the invention may also be administered directly to the eye or ear, typically in the form of drops of a micronised suspension or solution in isotonic, pH- adjusted, sterile saline.
  • Other formulations suitable for ocular and aural administration include ointments, biodegradable (e.g. absorbable gel sponges, collagen) and non- biodegradable (e.g. silicone) implants, wafers, lenses and particulate or vesicular systems, such as niosomes or liposomes.
  • a polymer such as crossed-linked polyacrylic acid, polyvinylalcohol, hyaluronic acid, a cellulosic polymer, for example,
  • hydroxypropylmethylcellulose, hydroxyethylcellulose, or methyl cellulose, or a heteropolysaccharide polymer, for example, gelan gum may be incorporated together with a preservative, such as benzalkonium chloride.
  • a preservative such as benzalkonium chloride.
  • Such formulations may also be delivered by iontophoresis.
  • the compounds of the invention may be combined with soluble macromolecular entities, such as cyclodextrin and suitable derivatives thereof or polyethylene glycol- containing polymers, in order to improve their solubility, dissolution rate, taste-masking, bioavailability and/or stability for use in any of the aforementioned modes of
  • Drug-cyclodextrin complexes are found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes may be used.
  • the cyclodextrin may be used as an auxiliary additive, i.e. as a carrier, diluent, or solubiliser. Most commonly used for these purposes are alpha-, beta- and gamma-cyclodextrins, examples of which may be found in International Patent Applications Nos. WO
  • the total daily dose of the compounds of the invention is typically in the range 1 mg to 10g, such as 10mg to 1 g, for example 25mg to 500mg depending, of course, on the mode of administration and efficacy.
  • oral administration may require a total daily dose of from 50mg to 100mg.
  • the total daily dose may be administered in single or divided doses and may, at the physician's discretion, fall outside of the typical range given herein. These dosages are based on an average human subject having a weight of about 60kg to 70kg. The physician will readily be able to determine doses for subjects whose weight falls outside this range, such as infants and the elderly.
  • the compounds of the invention are useful because they exhibit pharmacological activity in animals, i.e., mPGES-1 inhibition. More particularly, the compounds of the invention are of use in the treatment of disorders for which a mPGES-1 inhibitor is indicated.
  • the animal is a mammal, more preferably a human.
  • a compound of the invention for the treatment of a disorder for which a mPGES-1 inhibitor is indicated.
  • a method of treating a disorder in an animal comprising administering to said animal a therapeutically effective amount of a compound of the invention.
  • Thallium pain is an important protective mechanism designed to warn of danger from potentially injurious stimuli from the external environment.
  • the system operates through a specific set of primary sensory neurones and is activated by noxious stimuli via peripheral transducing mechanisms (see Millan, 1999, Prog. Neurobiol., 57, 1-164 for a review). These sensory fibres are known as nociceptors and are
  • Nociceptors encode the intensity, duration and quality of noxious stimulus and by virtue of their topographically organised projection to the spinal cord, the location of the stimulus.
  • the nociceptors are found on nociceptive nerve fibres of which there are two main types, A- delta fibres (myelinated) and C fibres (non-myelinated).
  • the activity generated by nociceptor input is transferred, after complex processing in the dorsal horn, either directly, or via brain stem relay nuclei, to the ventrobasal thalamus and then on to the cortex, where the sensation of pain is generated.
  • Pain may generally be classified as acute or chronic. Acute pain begins suddenly and is short-lived (usually twelve weeks or less). It is usually associated with a specific cause such as a specific injury and is often sharp and severe. It is the kind of pain that can occur after specific injuries resulting from surgery, dental work, a strain or a sprain. Acute pain does not generally result in any persistent psychological response. In contrast, chronic pain is long-term pain, typically persisting for more than three months and leading to significant psychological and emotional problems. Common examples of chronic pain are neuropathic pain (e.g. painful diabetic neuropathy, postherpetic neuralgia), carpal tunnel syndrome, back pain, headache, cancer pain, arthritic pain and chronic post-surgical pain.
  • neuropathic pain e.g. painful diabetic neuropathy, postherpetic neuralgia
  • carpal tunnel syndrome e.g. painful diabetic neuropathy, postherpetic neuralgia
  • back pain e.g. painful diabetic neuropathy, postherpetic neuralgia
  • nociceptor activation When a substantial injury occurs to body tissue, via disease or trauma, the characteristics of nociceptor activation are altered and there is sensitisation in the periphery, locally around the injury and centrally where the nociceptors terminate.
  • Pain can also therefore be divided into a number of different subtypes according to differing pathophysiology, including nociceptive, inflammatory and neuropathic pain.
  • Nociceptive pain is induced by tissue injury or by intense stimuli with the potential to cause injury. Pain afferents are activated by transduction of stimuli by nociceptors at the site of injury and activate neurons in the spinal cord at the level of their termination. This is then relayed up the spinal tracts to the brain where pain is perceived (Meyer et al., 1994, Textbook of Pain, 13-44). The activation of nociceptors activates two types of afferent nerve fibres. Myelinated A-delta fibres transmit rapidly and are responsible for sharp and stabbing pain sensations, whilst unmyelinated C fibres transmit at a slower rate and convey a dull or aching pain.
  • Moderate to severe acute nociceptive pain is a prominent feature of pain from central nervous system trauma, strains/sprains, burns, myocardial infarction and acute pancreatitis, post-operative pain (pain following any type of surgical procedure), posttraumatic pain, renal colic, cancer pain and back pain.
  • Cancer pain may be chronic pain such as tumour related pain (e.g. bone pain, headache, facial pain or visceral pain) or pain associated with cancer therapy (e.g. postchemotherapy syndrome, chronic postsurgical pain syndrome or post radiation syndrome). Cancer pain may also occur in response to chemotherapy, immunotherapy, hormonal therapy or radiotherapy.
  • Back pain may be due to herniated or ruptured intervertebral discs or abnormalities of the lumber facet joints, sacroiliac joints, paraspinal muscles or the posterior longitudinal ligament. Back pain may resolve naturally but in some patients, where it lasts over 12 weeks, it becomes a chronic condition which can be particularly debilitating.
  • Neuropathic pain is currently defined as pain initiated or caused by a primary lesion or dysfunction in the nervous system. Nerve damage can be caused by trauma and disease and thus the term 'neuropathic pain' encompasses many disorders with diverse aetiologies. These include, but are not limited to, peripheral neuropathy, diabetic neuropathy, post herpetic neuralgia, trigeminal neuralgia, back pain, cancer neuropathy, HIV neuropathy, phantom limb pain, carpal tunnel syndrome, central post- stroke pain and pain associated with chronic alcoholism, hypothyroidism, uremia, multiple sclerosis, spinal cord injury, Parkinson's disease, epilepsy and vitamin deficiency. Neuropathic pain is pathological as it has no protective role.
  • neuropathic pain are difficult to treat, as they are often heterogeneous even between patients with the same disease (Woolf & Decosterd, 1999, Pain Supp., 6, S141 -S147; Woolf and Mannion, 1999, Lancet, 353, 1959-1964). They include spontaneous pain, which can be continuous, and paroxysmal or abnormal evoked pain, such as hyperalgesia (increased sensitivity to a noxious stimulus) and allodynia (sensitivity to a normally innocuous stimulus).
  • the inflammatory process is a complex series of biochemical and cellular events, activated in response to tissue injury or the presence of foreign substances, which results in swelling and pain (Levine and Taiwo, 1994, Textbook of Pain, 45-56).
  • Arthritic pain is the most common inflammatory pain.
  • Rheumatoid disease is one of the commonest chronic inflammatory conditions in developed countries and rheumatoid arthritis is a common cause of disability. The exact aetiology of rheumatoid arthritis is unknown, but current hypotheses suggest that both genetic and microbiological factors may be important (Grennan & Jayson, 1994, Textbook of Pain, 397-407).
  • Ankylosing spondylitis is also a rheumatic disease that causes arthritis of the spine and sacroiliac joints. It varies from intermittent episodes of back pain that occur throughout life to a severe chronic disease that attacks the spine, peripheral joints and other body organs.
  • Visceral pain is pain associated with the viscera, which encompass the organs of the abdominal cavity. These organs include the sex organs, spleen and part of the digestive system. Pain associated with the viscera can be divided into digestive visceral pain and non-digestive visceral pain.
  • Gl gastrointestinal
  • FBD functional bowel disorder
  • IBD inflammatory bowel disease
  • Gl disorders include a wide range of disease states that are currently only moderately controlled, including, in respect of FBD, gastro-esophageal reflux, dyspepsia, irritable bowel syndrome (IBS) and functional abdominal pain syndrome (FAPS), and, in respect of IBD, Crohn's disease, ileitis and ulcerative colitis, all of which regularly produce visceral pain.
  • Other types of visceral pain include the pain associated with dysmenorrhea, cystitis and pancreatitis and pelvic pain.
  • heart and vascular pain including pain caused by angina, myocardical infarction, mitral stenosis, pericarditis, Raynaud's phenomenon, scleredoma and skeletal muscle ischemia;
  • head pain such as migraine (including migraine with aura and migraine without aura), cluster headache, tension-type headache mixed headache and headache associated with vascular disorders; and
  • ⁇ orofacial pain including dental pain, otic pain, burning mouth syndrome and
  • Neoplasias that produce PGs include brain cancer, bone cancer, epithelial cell derived neoplasia (epithelial carcinoma) such as basal cell carcinoma, adenocarcinoma, gastrointestinal cancer such as lip cancer, mouth cancer, esophogeal cancer, small bowel cancer and stomach cancer, colon cancer, liver cancer, bladder cancer, pancreatic cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer and skin cancer, such as squamus cell and basal cell cancers, prostate cancer, renal cell carcinoma, and other known cancers that effect epithelial cells throughout the body.
  • the compounds of the invention can also be used to treat the fibrosis which occurs with radiation therapy and adenomatous polyps, including familial adenomatous polyposis (FAP).
  • FAP familial adenomatous polyposis
  • a mPGES-1 inhibitor may be usefully combined with another pharmacologically active compound, or with two or more other pharmacologically active compounds, particularly in the treatment of pain. Such combinations offer the possibility of significant advantages, including patient compliance, ease of dosing and synergistic activity.
  • the mPGES-1 inhibitor of formula (I), or a pharmaceutically acceptable salt thereof, as defined above may be administered simultaneously, sequentially or separately in combination with one or more agents selected from:
  • ⁇ an inhibitor of nerve growth factor signaling, such as: an agent that binds to NGF and inhibits NGF biological activity and/or downstream pathway(s) mediated by NGF signaling (e.g. tanezumab), a TrkA antagonist or a p75 antagonist;
  • a sodium channel modulator such as lidocaine
  • a Nav1.7 channel modulator for example one or more compounds disclosed in WO2009/012242
  • an alternative sodium channel modulator such as a Nav1 .3 modulator (e.g. those disclosed in WO2008/1 18758); or a Nav1.8 modulator (e.g. those disclosed in WO 2008/135826, such as N-[6-Amino-5-(2-chloro-5-methoxyphenyl)pyridin-2-yl]-1 - methyl-1 H-pyrazole-5-carboxamide
  • a sodium channel modulator such as lidocaine
  • a Nav1.7 channel modulator for example one or more compounds disclosed in WO2009/012242
  • a compound which increases the levels of endocannabinoid such as a compound with fatty acid amid hydrolase inhibitory (FAAH) activity, in particular those disclosed in WO 2008/047229 (e.g. N-pyridazin-3-yl-4-(3- ⁇ [5-(trifluoromethyl)pyridine-2- yl]oxy ⁇ benzylidene)piperidene-1-carboxamide);
  • FAAH fatty acid amid hydrolase inhibitory
  • an opioid analgesic e.g. morphine, heroin, hydromorphone, oxymorphone
  • levorphanol levallorphan, methadone, meperidine, fentanyl, cocaine, codeine, dihydrocodeine, oxycodone, hydrocodone, propoxyphene, nalmefene, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol, nalbuphine or pentazocine;
  • NSAID nonsteroidal antiinflammatory drug
  • NSAID nonsteroidal antiinflammatory drug
  • diclofenac diflusinal, etodolac
  • fenbufen fenoprofen
  • flufenisal flurbiprofen
  • ibuprofen indomethacin
  • ketoprofen ketorolac
  • meclofenamic acid mefenamic acid
  • meloxicam nabumetone, naproxen, nimesulide, nitroflurbiprofen, olsalazine, oxaprozin, phenylbutazone, piroxicam, sulfasalazine, sulindac, tolmetin or zomepirac
  • NSAID nonsteroidal antiinflammatory drug
  • a barbiturate sedative e.g. amobarbital, aprobarbital, butabarbital, butabital,
  • mephobarbital metharbital, methohexital, pentobarbital, phenobartital, secobarbital, talbutal, theamylal or thiopental;
  • a benzodiazepine having a sedative action e.g. chlordiazepoxide, clorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam or triazolam;
  • an Hi antagonist having a sedative action e.g. diphenhydramine, pyrilamine,
  • promethazine chlorpheniramine or chlorcyclizine
  • ⁇ a sedative such as glutethimide, meprobamate, methaqualone or
  • a skeletal muscle relaxant e.g. baclofen, carisoprodol, chlorzoxazone,
  • an NMDA receptor antagonist e.g. dextromethorphan ((+)-3-hydroxy-N- methylmorphinan) or its metabolite dextrorphan ((+)-3-hydroxy-N-methylmorphinan), ketamine, memantine, pyrroloquinoline quinine, cis-4-(phosphonomethyl)-2- piperidinecarboxylic acid, budipine, EN-3231 (MorphiDex®, a combination formulation of morphine and dextromethorphan), topiramate, neramexane or perzinfotel including an NR2B antagonist, e.g.
  • an NMDA receptor antagonist e.g. dextromethorphan ((+)-3-hydroxy-N- methylmorphinan) or its metabolite dextrorphan ((+)-3-hydroxy-N-methylmorphinan), ketamine, memantine, pyrroloquinoline quinine, cis-4-(phosphonomethyl
  • an alpha-adrenergic e.g. doxazosin, tamsulosin, clonidine, guanfacine,
  • dexmetatomidine modafinil, or 4-amino-6,7-dimethoxy-2-(5-methane-sulfonamido- 1 ,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl) quinazoline;
  • a tricyclic antidepressant e.g. desipramine, imipramine, amitriptyline or nortriptyline;
  • an anticonvulsant e.g. carbamazepine, lamotrigine, topiratmate or valproate;
  • a tachykinin (NK) antagonist particularly an NK-3, NK-2 or NK-1 antagonist, e.g.
  • COX-2 selective inhibitor e.g. celecoxib, rofecoxib, parecoxib, valdecoxib,
  • a neuroleptic such as droperidol, chlorpromazine, haloperidol, perphenazine,
  • thioridazine mesoridazine, trifluoperazine, fluphenazine, clozapine, olanzapine, risperidone, ziprasidone, quetiapine, sertindole, aripiprazole, sonepiprazole, blonanserin, iloperidone, perospirone, raclopride, zotepine, bifeprunox, asenapine, lurasidone, amisulpride, balaperidone, palindore, eplivanserin, osanetant, rimonabant, meclinertant, Miraxion® or sarizotan;
  • a vanilloid receptor agonist e.g. resinf era toxin
  • antagonist e.g. capsazepine
  • a beta-adrenergic such as propranolol
  • ⁇ a corticosteroid such as dexamethasone
  • a 5-HT receptor agonist or antagonist particularly a 5-HTI B /I D agonist such as
  • a 5-HT 2A receptor antagonist such as R(+)-alpha-(2,3-dimethoxy-phenyl)-1-[2-(4- fluorophenylethyl)]-4-piperidinemethanol (MDL-100907);
  • ⁇ a 5-HT 3 antagonist such as ondansetron
  • a cholinergic (nicotinic) analgesic such as ispronicline (TC-1734), (E)-N-methyl-4-(3- pyridinyl)-3-buten-1 -amine (RJR-2403), (R)-5-(2-azetidinylmethoxy)-2-chloropyridine (ABT-594) or nicotine;
  • a PDEV inhibitor such as 5-[2-ethoxy-5-(4-methyl-1-piperazinyl-sulphonyl)phenyl]-1- methyl-3-n-propyl-1 ,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (sildenafil), (6R,12aR)-2,3,6,7, 12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)- pyrazino[2', 1 ':6, 1]-pyrido[3,4-b]indole-1 ,4-dione (IC-351 or tadalafil), 2-[2-ethoxy-5- (4-ethyl-piperazin-1-yl-1-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5, 1- f][1 ,2,4]triazin-4-one (vardenafil), 5-(2-e
  • an alpha-2-delta ligand such as gabapentin, pregabalin, 3-methylgabapentin,
  • mGluRI metabotropic glutamate subtype 1 receptor
  • a serotonin reuptake inhibitor such as sertraline, sertraline metabolite
  • demethylsertraline fluoxetine, norfluoxetine (fluoxetine desmethyl metabolite), fluvoxamine, paroxetine, citalopram, citalopram metabolite desmethylcitalopram, escitalopram, d,l-fenfluramine, femoxetine, ifoxetine, cyanodothiepin, litoxetine, dapoxetine, nefazodone, cericlamine and trazodone;
  • noradrenaline noradrenaline (norepinephrine) reuptake inhibitor, such as maprotiline
  • Vivalan® especially a selective noradrenaline reuptake inhibitor such as reboxetine, in particular (S,S)-reboxetine;
  • a dual serotonin-noradrenaline reuptake inhibitor such as venlafaxine, venlafaxine metabolite O-desmethylvenlafaxine, clomipramine, clomipramine metabolite desmethylclomipramine, duloxetine, milnacipran and imipramine;
  • an inducible nitric oxide synthase (iNOS) inhibitor such as S-[2-[(1- iminoethyl)amino]ethyl]-L-homocysteine, S-[2-[(1-iminoethyl)-amino]ethyl]-4,4-dioxo-
  • iNOS inducible nitric oxide synthase
  • an acetylcholinesterase inhibitor such as donepezil
  • a prostaglandin E 2 subtype 4 (EP4) antagonist such as A/-[( ⁇ 2-[4-(2-ethyl-4,6- dimethyl-1 H-imidazo[4,5-c]pyridin-1 -yl)phenyl]ethyl ⁇ amino)-carbonyl]-4- methylbenzenesulfonamide or 4-[(1 S)-1 -( ⁇ [5-chloro-2-(3-fluorophenoxy)pyridin-3- yl]carbonyl ⁇ amino)ethyl]benzoic acid; or
  • a leukotriene B4 antagonist such as 1-(3-biphenyl-4-ylmethyl-4-hydroxy-chroman-7- yl)-cyclopentanecarboxylic acid (CP-105696), 5-[2-(2-Carboxyethyl)-3-[6-(4- methoxyphenyl)-5E- hexenyl]oxyphenoxy]-valeric acid (ONO-4057) or DPC-1 1870,
  • a 5-lipoxygenase inhibitor such as zileuton, 6-[(3-fluoro-5-[4-methoxy-3, 4,5,6- tetrahydro-2H-pyran-4-yl])phenoxy-methyl]-1-methyl-2-quinolone (ZD-2138), or 2,3,5-trimethyl-6-(3-pyridylmethyl),1 ,4-benzoquinone (CV-6504).
  • a compound of the invention together with one or more additional therapeutic agents which slow down the rate of metabolism of the compound of the invention, thereby leading to increased exposure in patients.
  • Increasing the exposure in such a manner is known as boosting.
  • This has the benefit of increasing the efficacy of the compound of the invention or reducing the dose required to achieve the same efficacy as an unboosted dose.
  • the metabolism of the compounds of the invention includes oxidative processes carried out by P450 (CYP450) enzymes, particularly CYP 3A4 and conjugation by UDP glucuronosyl transferase and sulphating enzymes.
  • agents that may be used to increase the exposure of a patient to a compound of the present invention are those that can act as inhibitors of at least one isoform of the cytochrome P450 (CYP450) enzymes.
  • the isoforms of CYP450 that may be beneficially inhibited include, but are not limited to, CYP1A2, CYP2D6, CYP2C9, CYP2C19 and CYP3A4.
  • Suitable agents that may be used to inhibit CYP 3A4 include ritonavir, saquinavir, ketoconazole, N-(3,4-difluorobenzyl)-N-methyl-2- ⁇ [(4- methoxypyridin-3-yl)amino]sulfonyl ⁇ benzamide and N-(1-(2-(5-(4-fluorobenzyl)-3- (pyridin-4-yl)-1 H-pyrazol-1-yl)acetyl)piperidin-4-yl)methanesulfonamide.
  • kits of the invention comprises two or more separate
  • kits for separately retaining said compositions, such as a container, divided bottle, or divided foil packet.
  • An example of such a kit is the familiar blister pack used for the packaging of tablets, capsules and the like.
  • the kit of the invention is particularly suitable for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another.
  • the kit typically comprises directions for administration and may be provided with a so-called memory aid.
  • the invention provides a pharmaceutical product (such as in the form of a kit) comprising a compound of the invention together with one or more additional therapeutically active agents as a combined preparation for simultaneous, separate or sequential use in the treatment of a disorder for which a mPGES-1 inhibitor is indicated.
  • a 465 base pair cDNA encoding human mPGES-1 was amplified by polymerase chain reaction from an in-house library of human testis DNA.
  • the oligonucleotide primers incorporated Ncol and EcoRI restriction sites 5' and 3' of the coding region, respectively, which were used to clone the cDNA into the pENTR4 vector from
  • Sf9 insect cells were transfected with the baculoviral DNA containing mPGES-1 using Cellfectin® reagent and standard protocol. After 3-5 days, the supernatant medium contained infectious recombinant virus particles capable of expressing mPGES-1 . A larger stock of this virus was prepared by infecting fresh Sf9 cells, titered, and then used for protein expression. Conditions for expression were determined by a small scale optimization study followed by Western analysis of expressed protein using Cayman (Ann Arbor, Ml) anti- mPGES-1 Ab (data not shown). For expression, Sf9 cells were seeded at 1 x 10e6 cells/mL and infected with virus at a multiplicity of infection of 0.1. At 48 hours post-infection, the cells were harvested, and the pellets stored at -80°C.
  • PGE 2 by mPGES-1 was assessed by incubation of enzyme with 2 uM PGH 2 for 41 seconds at room temperature and assessment of PGE 2 by Enzyme Linked Immunosorbant Assay (ELISA).
  • Enzyme is suspended in assay buffer comprised of 100 mM KP0 4 pH 6.2 (stock pH), 2.5 mM glutathione at a dilution that produces approximately 100-150 ng/ml PGE 2 (approximately 15 to 20% conversion of substrate to product), typically about 400-800x.
  • PGH 2 (Cayman Chemical, Ann Arbor Ml) is diluted 12.8 x in ice cold 10 mM HCI from a 278 uM stock in acetone.
  • the reaction is begun by the addition of 1 :10 volume of PGH 2 to the enzyme inhibitor mixture for a final concentration of 2 uM.
  • the reaction is terminated by the addition of 1 :10 volumes of 2.5 mM FeCI 2 (Final concentration, a 25 mM stock FeCI 2 is made-up fresh in 50 mM citric acid and sonicated).
  • the reaction is immediately diluted 120 x into ELISA buffer (according to Cayman Chemical, Ann Arbor Ml recipe).
  • PGE 2 formed was calculated from a standard curve of PGE 2 by ELISA (Cayman Chemical, Ann Arbor Ml).
  • the % control activity was calculated as the percentage difference between negative control (100% inhibited with a reference compound) and enzyme only control.
  • the difference between enzymatic vs. non-enzymatic production of PGE2 are typically 3-4 fold.
  • ICso's are calculated by 4 parameter log fit of the % control data.
  • the compound of formula (I) was tested in a beagle whole blood assay at 7 drug concentrations.
  • a 96 well plate was used for the mPGEsl assay (ELISA plate).
  • Blood was drawn from 1 batch of three dogs, from which mPGESI assay was developed for the compound of formula (I).
  • the compound was dispensed into 3 columns on a Blood plate for each animal. 3 columns are no drug controls with one of these also being a no LPS control (columns 4, 1 1 and 12, respectively).
  • Plasma drawn from the blood plates are then diluted and transferred to 3 ELISA plates, with compounds randomized to two locations (columns 4-6 and 8-10) on an ELISA plate.
  • Plasma or Serum Analysis of mPGESI (in vitro): All samples were thawed and then assayed together on the same day. mPGESI inhibitions were determined using EIA kits from Cayman Chemical. Prostaglandin E 2 (PGE2) was used to determine the activity of COX-2. (Samples of the positive control plasma were assayed in a preliminary ELISA assay to determine the best dilution for each animal. Using the EIA kit buffer, several dilutions are made; (tested at 1 :100, 1 :500, 1 :1000 and 1 :2000). The primary ELISA assay is performed using the best dilution factor for each animal.
  • the mPGES-1 inhibitor of the compound of formula (I) showed an IC50 value of 90 nM and an IC90 value of close to 1 uM when measuring inhibition of PGE2 production.
  • Step 3 Preparation of 2, 5-dichloro-1 ,3-benzoxazole.
  • Step 4 Preparation of ethyl 1 -(5-chloro-1 ,3-benzoxazol-2-yl)piperidine-4-carboxylate.
  • Step 5 Preparation of Ethyl 1 -(6-bromo-5-chloro-1 ,3-benzoxazol-2-yl)piperidine-4- carboxylate
  • Step 6 Preparation of ethyl 1-[5-chloro-6-(4-chlorophenyl)-1 ,3-benzoxazol-2- yl]piperidine-4-carboxylate
  • Step 7 Preparation of 1 -[5-Chloro-6-(4-chlorophenyl)-1 ,3-benzoxazol-2-yl]piperidine-4- carboxylic acid
  • Step 8 Preparation of 1-[5-Chloro-6-(4-chlorophenyl)-1 ,3-benzoxazol-2-yl]-N-[(1 S,3S)- 3-(hydroxymethyl)cyclohexyl]piperidine-4-carboxamide

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Abstract

La présente invention concerne des pipéridinecarboxamides de formule (I), leur utilisation en médecine en tant qu'inhibiteurs de mPGES - 1 pour le traitement de la douleur, des compositions les contenant, des procédés pour leur préparation et des intermédiaires utilisés dans de tels procédés.
PCT/IB2010/055736 2009-12-22 2010-12-10 Pipéridinecarboxamides en tant qu'inhibiteurs de mpges - 1 WO2011077313A1 (fr)

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WO2013146970A1 (fr) * 2012-03-29 2013-10-03 第一三共株式会社 Nouveau dérivé de quinoléine
CN104327061A (zh) * 2014-10-19 2015-02-04 湖南华腾制药有限公司 一种溴苯并[d]恶唑衍生物的制备方法
WO2016016861A1 (fr) * 2014-08-01 2016-02-04 Glenmark Pharmaceuticals S.A. Formulation nanoparticulaire comprenant un inhibiteur de mpges -1

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EP3517104A1 (fr) * 2014-08-01 2019-07-31 Glenmark Pharmaceuticals S.A. Formulation nanoparticulaire comprenant un inhibiteur de mpges -1
CN104327061A (zh) * 2014-10-19 2015-02-04 湖南华腾制药有限公司 一种溴苯并[d]恶唑衍生物的制备方法

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