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WO2008135767A1 - Nouveaux composés de triazole pour le traitement d'inflammations - Google Patents

Nouveaux composés de triazole pour le traitement d'inflammations Download PDF

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Publication number
WO2008135767A1
WO2008135767A1 PCT/GB2008/001583 GB2008001583W WO2008135767A1 WO 2008135767 A1 WO2008135767 A1 WO 2008135767A1 GB 2008001583 W GB2008001583 W GB 2008001583W WO 2008135767 A1 WO2008135767 A1 WO 2008135767A1
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WIPO (PCT)
Prior art keywords
compound
triazole
treatment
compounds
disease
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PCT/GB2008/001583
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English (en)
Inventor
Benjamin Pelcman
Andrei Sanin
Peter Nilsson
Hasse Kromann
Lena Pereswetoff-Morath
Mattias Andersson
Karol Horvath
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Biolipox Ab
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Publication of WO2008135767A1 publication Critical patent/WO2008135767A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
    • 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

  • This invention relates to new salts of pharmaceutically-active compounds, to pharmaceutical compositions containing them, and to processes for obtaining them.
  • the salts are useful in the inhibition of the activity of 15-lipoxygenase and thus in the treatment of inflammatory diseases and of inflammation generally.
  • the invention also relates to the use of such compounds as medicaments, to pharmaceutical compositions containing them, and to synthetic routes for their production.
  • Asthma is a chronic inflammatory disease affecting 6% to 8% of the adult population of the industrialized world. In children, the incidence is even higher, being close to 10% in most countries. Asthma is the most common cause of hospitalization for children under the age of fifteen.
  • Treatment regimens for asthma are based on the severity of the condition. Mild cases are either untreated or are only treated with inhaled ⁇ -agonists. Patients with more severe asthma are typically treated with anti-inflammatory compounds on a regular basis.
  • LTRas leukotriene receptor antagonists
  • Rhinitis, conjunctivitis and dermatitis may have an allergic component, but may also arise in the absence of underlying allergy. Indeed, non-allergic conditions of this class are in many cases more difficult to treat.
  • COPD chronic obstructive pulmonary disease
  • Inflammation is also a common cause of pain. Inflammatory pain may arise for numerous reasons, such as infection, surgery or other trauma. Moreover, several malignancies are known to have inflammatory components adding to the symptomatology of the patients. Thus, a new and/or alternative anti-inflammatory treatment would be of benefit to all of the above-mentioned patient groups. In particular, there is a real and substantial unmet clinical need for an effective anti-inflammatory drug capable of treating inflammatory disorders, such as asthma, with no real or perceived side effects.
  • the mammalian lipoxygenases are a family of structurally-related enzymes, which catalyze the oxygenation of arachidonic acid.
  • Three types of human lipoxygenases are known, which catalyze the insertion of molecular oxygen into arachidonic acid at carbon positions 5, 12 and 15.
  • the enzymes are thus named 5-, 12- and 15-lipoxygenase, respectively.
  • Arachidonic acid metabolites that are formed following the action of lipoxygenases are known to have pronounced pathophysiological activity including pro-inflammatory effects.
  • the primary product of the action of 5-lipoxygenase on arachidonic acid is further converted by a number of enzymes to a variety of physiologically and pathophysiologically important metabolites.
  • the most important of these, the leukotrienes are strong bronchoconstrictors.
  • Huge efforts have been devoted towards the development of drugs that inhibit the action of these metabolites as well as the biological processes that form them.
  • Drugs that have been developed to this end include 5-lipoxygenase inhibitors, inhibitors of FLAP (Five Lipoxygenase Activating Protein) and, as mentioned previously, leukotriene receptor antagonists (LTRas).
  • arachidonic acid metabolites that are produced by this process include prostaglandins, thromboxanes and prostacyclin, all of which possess physiological or pathophysiological activity.
  • the prostaglandin PGE 2 is a strong pro-inflammatory mediator, which also induces fever and pain. Consequently, a number of drugs have been developed to inhibit the formation of PGE 2 , including "NSAIDs” (non-steroidal antiinflammatory drugs) and “coxibs” (selective cyclooxygenase-2 inhibitors). These classes of compounds act predominantly by way of inhibition of one or several cyclooxygenases.
  • agents that are capable of blocking the formation of arachidonic acid metabolites are likely to be of benefit in the treatment of inflammation.
  • salt formation has the effect of rendering a drug substance water-soluble by presenting it in ionized form in aqueous media, particularly in situations when corresponding free acids and bases are insoluble. This in itself is likely to result in an improved dissolution profile and therefore enhanced bioavailability.
  • Additional advantages may include improved physico-chemical stability, for example by prevention of polymorphism (i.e. potentially giving rise to a single thermodynamically- and chemically-stable solid state form).
  • salts may also give rise to processing advantages, such as ease of isolation and purification following formation. Such factors are of importance, not only from the point of view of obtaining a commercially viable manufacturing process, but also from the point of view of subsequent manufacture of pharmaceutical formulations comprising the active compound.
  • X 1 and X 2 independently represents F, Cl, OCF 3 , CF 3 , CHF 2 Or OCHF 2 ;
  • a moiety B which moiety comprises a metal, an organic amine or a basic amino acid
  • Compounds of the invention are formed by an association between moieties A and B.
  • compounds of the invention comprise an association between moieties defined by A and B above.
  • the aforementioned association between moieties A and B may be any kind of physico-chemical association (i.e. interaction or bonding) between the respective moieties, for example an ionic association (wholly or in part), so forming a salt, or one or more other kinds of association (wholly or in part), such as a covalent (including polar covalent and coordinate covalent) association, a metallic association, or another, electrostatic association, such as a permanent dipole to permanent dipole interaction, hydrogen bonding, van der Waals forces and/or a cation-pi interaction. It is however preferred that the association is at least partly ionic, so forming a salt of formula
  • X 1 and X 2 independently represent H, F, Cl, OCF 3 , CF 3 , OCHF 2 or CHF 2 , although X 1 and X 2 both cannot both represent H.
  • Preferred compounds of formula I include those in which at least one of X 1 and X 2 independently represents F, Cl or OCF 3 .
  • More preferred compounds of formula I include:
  • Preferred metals that may form moiety B in a compound of the invention include mineral bases, such as zinc, aluminium, alkaline earth metals and, preferably, alkali metals.
  • Preferred alkaline earth metals include magnesium and calcium.
  • Preferred alkali metals include lithium, more preferably sodium and, particularly, potassium.
  • Preferred organic amines that may form moiety B in a compound of the invention include benethamine, piperazine, ethylenediamine, 1 /-/-imidazole, morpholine, A- (2-hydroxyethyl)morpholine, triethanolamine, tromethamine, glucamine, N- methylglucamine, dimethylaminoethanol (deanol), procaine, ammonia, diethanolamine, 1-(2-hydroxyethyl)pyrrolidine, pyrrolidine, A- phenylcyclohexylamine, 2-aminoethanol, 2-(diethylamino)ethanol, benzathine, diethylamine, triethylamine, hydrabamine, TRIS (tris(hydroxymethyl)amino- methane), piperidine, ethanolamine, diethanolamine, triethanolamine, benzylamine, p-aminobenzoic acid, 2-diethyl aminoethyl ester, 1-ethyl
  • Preferred basic amino acids that may form moiety B in a compound of the invention include lysine, histadine, betaines (such as N,N,N-trimethylglycine) and L-arginine.
  • Compounds of the invention may thus contain double bonds and may thus exist as E ⁇ entadel) and Z (z ⁇ sammen) geometric isomers about each individual double bond. All such isomers and mixtures thereof are included within the scope of the invention.
  • Compounds of the invention may thus also contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereoisomerism. Diastereoisomers may be separated using conventional techniques. All stereoisomers and mixtures thereof are included within the scope of the invention.
  • Compounds of the invention may be obtained by way of standard techniques, for example by reaction of a moiety A with a moiety B.
  • this may involve reaction of a moiety A with the requisite number of (e.g. one or more) equivalents of an appropriate base that either is a moiety B, or is capable of providing moiety B (e.g. in the case of an alkali metal, and alkali metal hydroxide etc.), optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of said solvent, or said medium, using standard techniques (e.g. in vacuo, by freeze-drying or by filtration).
  • Salts may also be prepared by exchanging a counter-ion of a compound of formula I that is already in the form of a salt with another counter- ion, for example using a suitable ion exchange resin. Processes of salt formation are described in detail hereinafter.
  • W is a structural fragment as represented by
  • squiggly line represents the point of attachment (e.g. to the -NH 2 group in, in this case, the compound of formula II) and X 1 and X 2 are as hereinbefore defined under coupling conditions, for example at around room temperature or above (e.g. up to 40-180 0 C), optionally in the presence of a suitable base (e.g.
  • 1 ,2,3-triazole-4- carboxylic acid may first be activated by treatment with a suitable reagent (e.g. oxalyl chloride, thionyl chloride, etc) optionally in the presence of an appropriate solvent (e.g. dichloromethane, THF, toluene or benzene) and a suitable catalyst (e.g. DMF), resulting in the formation of the respective acyl chloride.
  • a suitable reagent e.g. oxalyl chloride, thionyl chloride, etc
  • an appropriate solvent e.g. dichloromethane, THF, toluene or benzene
  • a suitable catalyst e.g. DMF
  • Alternative methods of performing this step include reaction of an O-protected derivative (e.g. an ethyl ester) of 1 ,2,3-triazole-4-carboxylic acid with a compound of formula II, which latter compound may first be treated with an appropriate reagent (e.g. trimethylaluminium), for example in an inert atmosphere and in the presence of a suitable solvent (e.g. dichloromethane);
  • an appropriate reagent e.g. trimethylaluminium
  • a suitable solvent e.g. dichloromethane
  • -OSO 2 CF 3 -B(OH) 2 , -Sn(R z ) 3 (wherein R z is C 1-6 alkyl and preferably, methyl or butyl), -Pb(OC(O)CH 3 ) 3 , -Bi(W) 2 , -Bi(W) 2 (OC(O)CH 3 ) 2 , -Bi(W) 2 (OC(O)CFa) 2 or -1(W)(BF 4 ), and W is as hereinbefore defined (and, where the compound of formula III contains more than one W group, they are preferably all the same), for example in the presence of a catalyst containing, preferably, Pd or Cu, and a base, such as potassium or sodium hydroxide, potassium carbonate, potassium terf-butoxide and lithium ⁇ /, ⁇ /-diisopropylamide.
  • a catalyst containing, preferably, Pd or Cu
  • a base such as potassium or sodium hydroxide, potassium carbonate
  • Catalysts that may be mentioned include Pd 2 (dba) 3 (tris(dibenzylideneacetone)- dipalladium(O)), bases that may be mentioned include cesium carbonate, ligands that may be mentioned include 2,2'-bis(diphenylphosphino)-1 ,1 '-binaphthyl and solvents that may be employed include toluene.
  • Such reactions may be performed at elevated temperature (e.g. at about 9O 0 C) under an inert (e.g. argon) atmosphere;
  • W is as hereinbefore defined, or a /V-protected derivative thereof, with a suitable reagent that provides a source of azide ions, such as sodium azide or trimethylsilyl azide, under conditions known to those skilled in the art.
  • a suitable reagent that provides a source of azide ions such as sodium azide or trimethylsilyl azide
  • the reaction may be performed under standard 1 ,3-dipolar cycloaddition reaction conditions, such as those described in Katritzky A.R. et al., Heterocycles 2003, 60 (5), 1225-1239.
  • the reaction may be performed without solvent or in the presence of an appropriate solvent (e.g.
  • W is as hereinbefore defined, followed by quenching with a suitable proton source (e.g. water or aqueous, saturated NH 4 CI solution).
  • a suitable proton source e.g. water or aqueous, saturated NH 4 CI solution.
  • a suitable proton source e.g. water or aqueous, saturated NH 4 CI solution.
  • the triazole may need to be protected at the nitrogen atom of the triazole ring system, preferably with a protective group that is also a directing metallation group (such as a SEM (i.e. a -CH 2 OC 2 H 4 Si(CH 3 ) 3 ) group).
  • the reaction may be performed in the presence of a suitable solvent, such as a polar aprotic solvent (e.g. tetrahydrofuran or diethyl ether), at sub-ambient temperatures (e.g.
  • a compound of formula Il as hereinbefore defined, for example under coupling conditions such as those described hereinbefore in respect of process step (i) above.
  • Preferred conditions include reaction in the presence of base, solvent but no coupling reagent.
  • the compound of formula Il may also be employed in excess.
  • 1 ,2,3-Triazole-4-carboxylic acid is commercially available (e.g. from Pfaltz &
  • W is as hereinbefore defined, under standard reduction conditions, for example, by employing tin (II) chloride dehydrate in the presence of an alcoholic solvent (e.g. ethanol) at reflux or by hydrogenation in the presence of a catalyst (e.g. palladium on carbon), with a source of hydrogen (e.g. hydrogen gas or nascent hydrogen (e.g. from ammonium formate)), optionally in the presence of a solvent (such as an alcoholic solvent (e.g. methanol)).
  • an alcoholic solvent e.g. ethanol
  • a catalyst e.g. palladium on carbon
  • hydrogen e.g. hydrogen gas or nascent hydrogen (e.g. from ammonium formate)
  • a solvent such as an alcoholic solvent (e.g. methanol)
  • 1 ,2,3-Triazole-4-carboxylic acid amide may be prepared by reaction of 1 ,2,3- triazole-4-carboxylic acid, or a derivative thereof, with ammonia, for example under reaction conditions such as those described hereinbefore in respect of preparation of compounds of formula I (process step (i) above).
  • Compounds of formula IV may be prepared by reaction of propiolic acid with a compound of formula Il as hereinbefore defined, for example under reaction conditions such as those described hereinbefore in respect of preparation of compounds of formula I (process step (i) above).
  • Compounds of formula Vl may be prepared from 1 ,2,3-triazole-4-carboxylic acid under dimerising conditions, for example in the presence of thionyl chloride or oxalyl chloride (optionally in the presence of a suitable solvent and catalyst, such as one hereinbefore defined in respect of process step (i)).
  • dimerising reagents include carbodiimides, such as 1.S-dicyclohexylcarbodiimide or 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide (EDCI, or hydrochloride thereof) optionally in the presence of a suitable base (e.g. 4-dimethylaminopyridine).
  • Substituents on W as hereinbefore defined may be modified one or more times, after or during the processes described above for preparation of compounds of formula I by way of methods that are well known to those skilled in the art. Examples of such methods include substitutions, reductions, oxidations, alkylations, hydrolyses and etherifications.
  • the precursor groups can be changed to a different such group, or to the groups defined in formula I, at any time during the reaction sequence.
  • the substituent on W is a halo group
  • such groups may be inter-converted one or more times, after or during the processes described above for the preparation of compounds of formula I.
  • Appropriate reagents include NiCI 2 (for the conversion to a chloro group).
  • the skilled person may also refer to "Comprehensive Organic Functional Group Transformations" by A. R. Katritzky, O. Meth-Cohn and C. W. Rees, Pergamon Press, 1995.
  • the functional groups of intermediate compounds may need to be protected by protecting groups.
  • the triazole nitrogen may need to be protected.
  • Suitable nitrogen-protecting groups include those which form:
  • carbamate groups i.e. alkoxy- or aryloxy-carbonyl groups
  • amide groups e.g. acetyl groups
  • /V-alkyl groups benzyl or SEM groups
  • ⁇ /-sulfonyl groups e.g. ⁇ /-arylsulfonyl groups
  • ⁇ /-phosphinyl and ⁇ /-phosphoryl groups e.g. diarylphosphinyl and diarylphosphoryl groups
  • ⁇ /-silyl group e.g. a /V-trimethylsifyl group.
  • Further protecting groups for the triazole nitrogen include a methyl group, which methyl group may be deprotected under standard conditions, such as employing a pyridine hydrochloride salt at elevated temperature, for example using microwave irradiation in a sealed vessel at 200 0 C.
  • the protection and deprotection of functional groups may take place before or after a reaction in the above-mentioned schemes.
  • Protecting groups may be removed in accordance with techniques that are well known to those skilled in the art and as described hereinafter. For example, protected compounds/intermediates described herein may be converted chemically to unprotected compounds using standard deprotection techniques.
  • Compounds of the invention may be obtained in crystalline form by way of a process that comprises crystallising a compound of the invention.
  • compounds of the invention may be crystallised with or without the presence of a solvent system (e.g. crystallisation may be from a melt, under supercritical conditions, or achieved by sublimation), we prefer that the crystallisation is from an appropriate solvent system.
  • a solvent system e.g. crystallisation may be from a melt, under supercritical conditions, or achieved by sublimation
  • the solvent system may include one or more organic solvents, such as alkyl acetates (e.g. linear or branched C 1-6 alkyl acetates, such as ethyl acetate, iso- propyl acetate and butyl acetate), lower (e.g. linear or branched C 1-6 , preferably
  • alkyl alcohols e.g. methanol, ethanol, isopropanol
  • aliphatic and aromatic hydrocarbons e.g. /so-octane, n-heptane, hexane and toluene
  • dialkyl ketones e.g. /so-octane, n-heptane, hexane and toluene
  • solvents may be employed as "antisolvents" (i.e. a solvent in which compounds of the invention are poorly soluble), and may thus aid the crystallisation process.
  • Crystallisation of compounds of the invention from an appropriate solvent system may be achieved by attaining supersaturation in a solvent system which comprises a compound of the invention (e.g. by cooling, by solvent evaporation, and/or via the addition of a suitable antisolvent).
  • concentration in solution of the compound that is to be crystallised may influence crystallisation temperatures and crystallisation times.
  • the compounds of the invention may also be in the form of a solvate, a hydrate or a mixed solvate/hydrate.
  • Compounds of the invention may also be in the form of an anhydrate.
  • anhydrate when used in this context, also includes compounds that are “ansolvates”.
  • Compounds of the invention that are anhydrates contain no more than 3%, preferably 1 % and more preferably 0.5% (w/w) water, whether such water is bound (crystal water or otherwise) or not.
  • Solvates, hydrates and mixed hydrates/solvates contain no less than 0.5 mol of solvent and/or water (as appropriate) per mol of compound of the invention.
  • Crystallisations may be carried out by seeding with nuclei and/or seed crystals of the desired crystalline form in the absence of nuclei and/or seed crystals of other crystalline forms.
  • Compounds of the invention may be isolated using techniques which are well known to those skilled in the art, for example decanting, filtering or centrifuging.
  • Compounds of the invention are useful because they comprise a moiety (moiety A) that possesses pharmacological activity. Compounds of the invention are therefore indicated as pharmaceuticals. According to a further aspect of the invention there is provided a compound of the invention for use as a pharmaceutical.
  • Compounds of the invention are useful because, in particular, they comprise a moiety (moiety A) that may inhibit the activity of lipoxygenases (and particularly 15-lipoxygenase), i.e. prevent the action of 15-lipoxygenase or a complex of which the 15-lipoxygenase enzyme forms a part and/or may elicit a 15- lipoxygenase modulating effect, for example as may be demonstrated in the test described below.
  • Compounds of the invention may thus be useful in the treatment of those conditions in which inhibition of a lipoxygenase, and particularly 15-lipoxygenase, is required.
  • Compounds of the invention are thus expected to be useful in the treatment of inflammation.
  • inflammation will be understood by those skilled in the art to include any condition characterised by a localised or a systemic protective response, which may be elicited by physical trauma, infection, chronic diseases, such as those mentioned hereinbefore, and/or chemical and/or physiological reactions to external stimuli (e.g. as part of an allergic response). Any such response, which may serve to destroy, dilute or sequester both the injurious agent and the injured tissue, may be manifest by, for example, heat, swelling, pain, redness, dilation of blood vessels and/or increased blood flow, invasion of the affected area by white blood cells, loss of function and/or any other symptoms known to be associated with inflammatory conditions.
  • inflammation will thus also be understood to include any inflammatory disease, disorder or condition per se, any condition that has an inflammatory component associated with it, and/or any condition characterised by inflammation as a symptom, including inter alia acute, chronic, ulcerative, specific, allergic and necrotic inflammation, and other forms of inflammation known to those skilled in the art.
  • the term thus also includes, for the purposes of this invention, inflammatory pain and/or fever.
  • compounds of the invention may be useful in the treatment of the following inflammatory diseases or conditions, and/or (if appropriate) inflammation that may be associated with such diseases or conditions: asthma, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, allergic disorders, rhinitis, inflammatory bowel disease, ulcers, inflammatory pain, fever, atherosclerosis, coronary artery disease, vasculitis, pancreatitis, arthritis, osteoarthritis, rheumatoid arthritis, conjunctivitis, ulceris, scleritis, uveitis, wound healing, dermatitis, eczema, psoriasis, stroke, diabetes, autoimmune diseases, Alzheimer's disease, multiple sclerosis, sarcoidosis, Hodgkin's disease and other malignancies, and any other disease with an inflammatory component.
  • COPD chronic obstructive pulmonary disease
  • pulmonary fibrosis allergic disorders, rhinitis, inflammatory bowel disease, ulcers,
  • Compounds of the invention may also be useful in the treatment of conditions that are not linked to inflammatory mechanisms, such as in the reduction of bone loss in a subject. Conditions that may be mentioned in this regard include osteoporosis, osteoarthritis, Paget's disease and/or periodontal diseases. Compounds of the invention may thus also be useful in increasing bone mineral density, as well as the reduction in incidence and/or healing of fractures, in subjects.
  • a method of treatment of a disease which is associated with, and/or which can be modulated by inhibition of, a lipoxygenase (such as 15-lipoxygenase), and/or a method of treatment of a disease in which inhibition of the activity of a lipoxygenase, and particularly 15-lipoxygenase, is desired and/or required (e.g. inflammation), which method comprises administration of a therapeutically effective amount of a compound of the invention to a patient suffering from, or susceptible to, such a condition.
  • a lipoxygenase such as 15-lipoxygenase
  • Patients include mammalian (including human) patients.
  • the term "effective amount” refers to an amount of a compound, which confers a therapeutic effect on the treated patient.
  • the effect may be objective (i.e. measurable by some test or marker) or subjective (i.e. the subject gives an indication of or feels an effect).
  • Compounds of the invention will normally be administered orally, intravenously, subcutaneously, intramuscularly, buccally, rectally, dermally, nasally, tracheally, bronchially, sublingually, by any other parenteral route or via inhalation, in a pharmaceutically acceptable dosage form.
  • Compounds of the invention may be administered alone, but are preferably administered by way of known pharmaceutical formulations, including tablets, capsules, powders, elixirs, suppositories, sterile solutions, sterile suspensions, or the like, for peroral and/or parenteral administration, or ointments or the like for dermal administration.
  • known pharmaceutical formulations including tablets, capsules, powders, elixirs, suppositories, sterile solutions, sterile suspensions, or the like, for peroral and/or parenteral administration, or ointments or the like for dermal administration.
  • Such formulations may be prepared in accordance with standard and/or accepted pharmaceutical practice.
  • a pharmaceutical formulation including a compound of the invention in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • the invention further provides a process for the preparation of a pharmaceutical formulation, as hereinbefore defined, which process comprises bringing into association a compound of the invention with a pharmaceutically-acceptable adjuvant, diluent or carrier.
  • Compounds of the invention may also be combined with other therapeutic agents that are useful in the treatment of inflammation as defined herein (e.g. NSAIDs, coxibs, corticosteroids, analgesics, inhibitors of 5-lipoxygenase, inhibitors of FLAP (5-lipoxygenase activating protein), and leukotriene receptor antagonists (LTRas), and/or other therapeutic agents that are useful in the treatment of inflammation).
  • NSAIDs e.g. NSAIDs, coxibs, corticosteroids, analgesics, inhibitors of 5-lipoxygenase, inhibitors of FLAP (5-lipoxygenase activating protein), and leukotriene receptor antagonists (LTRas)
  • NSAIDs e.g., piroxibs, corticosteroids, analgesics, inhibitors of 5-lipoxygenase, inhibitors of FLAP (5-lipoxygenase activating protein), and leukotriene receptor
  • a combination product comprising:
  • each of components (I) and (II) is formulated in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier.
  • Such combination products provide for the administration of compound of the invention in conjunction with the other therapeutic agent, and may thus be presented either as separate formulations, wherein at least one of those formulations comprises compound of the invention and at least one comprises the other therapeutic agent, or may be presented (i.e. formulated) as a combined preparation (i.e. presented as a single formulation including compound of the invention and the other therapeutic agent).
  • a pharmaceutical formulation including a compound of the invention, another therapeutic agent that is useful in the treatment of inflammation, and a pharmaceutically-acceptable adjuvant, diluent or carrier;
  • a pharmaceutical formulation including another therapeutic agent that is useful in the treatment of inflammation in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier, which components (a) and (b) are each provided in a form that is suitable for administration in conjunction with the other.
  • the invention further provides a process for the preparation of a combination product as hereinbefore defined, which process comprises bringing into association a compound of the invention with the other therapeutic agent that is useful in the treatment of inflammation, and at least one pharmaceutically- acceptable adjuvant, diluent or carrier.
  • the two components of the kit of parts may be: (i) provided as separate formulations (i.e. independently of one another), which are subsequently brought together for use in conjunction with each other in combination therapy; or (ii) packaged and presented together as separate components of a "combination pack" for use in conjunction with each other in combination therapy.
  • Oral, pulmonary and topical dosages may range from between about 0.01 mg/kg 1 of body weight per day (mg/kg/day) to about 100 mg/kg/day, preferably about 0.01 to about 10 mg/kg/day, and more preferably about 0.1 to about 5.0 mg/kg/day
  • compositions typically contain between about 0.01 mg to about 500 mg, and preferably between about 1 mg to about 100 mg, of the active ingredient (calculated as the amount of free compound of formula I as hereinbefore defined).
  • preferred doses will range from about 0.001 to about 10 mg/kg/hour (calculated as the amount of free compound of formula I as hereinbefore defined) during constant rate infusion.
  • compounds may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily.
  • the physician or the skilled person, will be able to determine the actual dosage which will be most suitable for an individual patient, which is likely to vary with the route of administration, the type and severity of the condition that is to be treated, as well as the species, age, weight, sex, renal function, hepatic function and response of the particular patient to be treated.
  • the above- mentioned dosages are exemplary of the average case; there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.
  • Compounds of the invention may have the advantage that they exhibit improved solubility and dissolution profiles in aqueous media when compared to corresponding free acids of formula I.
  • Compounds of the invention may also have the advantage that they exhibit improved physico-chemical stability (as described hereinbefore), and may give rise to processing advantages (e.g. ease of isolation and purification following their formation), when compared to corresponding free acids of formula I.
  • Compounds of the invention may aiso have the advantage that they may be more efficacious than, be less toxic than, be longer acting than, be more potent than, produce fewer side effects than, be more easily absorbed than, and/or have a better pharmacokinetic profile (e.g. higher oral bioavailability and/or lower clearance) than, and/or have other useful pharmacological, physical, or chemical properties over, compounds known in the prior art, whether for use in the stated indications or otherwise.
  • the assay employed takes advantage of the ability of lipoxygenases to oxidize polyunsaturated fatty acids, containing a 1 ,4-cis-pentadiene configuration, to their corresponding hydroperoxy or hydroxy! derivatives.
  • the lipoxygenase was a purified human 15-lipoxygenase and the fatty acid was arachidonic acid.
  • the assay is performed at room temperature (20-22 0 C) and the following are added to each well in a 96-well microtiter plate: a) 35 ⁇ l_ phosphate buffered saline (PBS) (pH 7.4); b) inhibitor (i.e.
  • Example C 950 nM
  • Example D 6980 nM
  • Example G 250 nM
  • NaOH 1.1 eq., 0.07 g, 50% aq.
  • MeOH 0.5 mL
  • MeOH 0.5 mL
  • Zinc chloride 0.5 eq., 0.75 g; 7% MeOH solution
  • the mixture was heated to 50 0 C.
  • the solution was allowed to reach rt and a precipitate was formed.
  • the precipitate was examined under polarized light with a microscope. The dry precipitate appeared to be amorphous while the wet (by water) precipitate appeared to be crystalline.
  • Example 8 The following compounds are prepared using analogous techniques to those described herein, for example in Examples 1 to 7:

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  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pain & Pain Management (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention porte sur un composé résultant d'une association entre : (i) un composé de formule (I), l'un au moins de ses substituants X1 et X2 du cycle phényle représentant (indépendamment) F, Cl, OCF3, CF3, CHF2Or OCHF2; et (ii) un métal, une amine organique ou un acide aminé basique. De tels composés sont utiles dans le traitement de maladies dans lesquelles on désire et/ou demande l'inhibition de l'activité d'une lipoxygénase (par exemple la15-lipoxygénase) et en particulier dans le traitement d'inflammations.
PCT/GB2008/001583 2007-05-07 2008-05-07 Nouveaux composés de triazole pour le traitement d'inflammations WO2008135767A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US92426307P 2007-05-07 2007-05-07
US60/924,263 2007-05-07
US671608P 2008-01-29 2008-01-29
US61/006,716 2008-01-29

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WO2008135767A1 true WO2008135767A1 (fr) 2008-11-13

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9073875B2 (en) 2012-11-20 2015-07-07 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of indoleamine 2,3-dioxygenase
CN111621026A (zh) * 2019-02-28 2020-09-04 南京农业大学 一种双功能钴配合物材料的制备方法及其电化学性能应用

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004080999A1 (fr) * 2003-03-14 2004-09-23 Biolipox Ab Composes de pyrazole utilises dans le traitement de l'inflammation

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004080999A1 (fr) * 2003-03-14 2004-09-23 Biolipox Ab Composes de pyrazole utilises dans le traitement de l'inflammation

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
TIHANYI E ET AL: "PYRAZOLECARBOXYLIC ACID HYDRAZIDES AS ANTIINFLAMMATORY AGENTS. NEW SELECTIVE LIPOXYGENASE INHIBITORS", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, EDITIONS SCIENTIFIQUE ELSEVIER, PARIS, FR, vol. 19, no. 5, 1984, pages 433 - 439, XP000942814, ISSN: 0223-5234 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9073875B2 (en) 2012-11-20 2015-07-07 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of indoleamine 2,3-dioxygenase
US9499497B2 (en) 2012-11-20 2016-11-22 Vertex Pharmaceuticals Incorporated Compounds useful as inhibitors of indoleamine 2,3-dioxygenase
CN111621026A (zh) * 2019-02-28 2020-09-04 南京农业大学 一种双功能钴配合物材料的制备方法及其电化学性能应用

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