WO2008135767A1

WO2008135767A1 - New triazole compounds useful in the treatment of inflammation

Info

Publication number: WO2008135767A1
Application number: PCT/GB2008/001583
Authority: WO
Inventors: Benjamin Pelcman; Andrei Sanin; Peter Nilsson; Hasse Kromann; Lena Pereswetoff-Morath; Mattias Andersson; Karol Horvath
Original assignee: Biolipox Ab
Priority date: 2007-05-07
Filing date: 2008-05-07
Publication date: 2008-11-13

Abstract

There is provided compound formed by an association between: (i) a compound of formula (I), wherein at least one of the substituents X1 and X2 on the phenyl ring represents (independently) F, Cl, OCF3, CF3, CHF2Or OCHF2; and (ii) a metal, an organic amine or a basic amino acid. Such compounds are useful in the treatment of diseases in which inhibition of the activity of a lipoxygenase (e.g. 15-lipoxygenase) is desired and/or required, and particularly in the treatment of inflammation.

Description

NEW TRIAZOLE COMPOUNDS USEFUL IN THE TREATMENT OF

INFLAMMATION

Field of the Invention

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.

Background of the Invention

There are many diseases/disorders that are inflammatory in their nature. One of the major problems associated with existing treatments of inflammatory conditions is a lack of efficacy and/or the prevalence of side effects (real or perceived).

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 β-agonists. Patients with more severe asthma are typically treated with anti-inflammatory compounds on a regular basis.

There is a considerable under-treatment of asthma, which is due at least in part to perceived risks with existing maintenance therapy (mainly inhaled corticosteroids). These include risks of growth retardation in children and loss of bone mineral density, resulting in unnecessary morbidity and mortality. As an alternative to steroids, leukotriene receptor antagonists (LTRas) have been developed. These drugs may be given orally, but are considerably less efficacious than inhaled steroids and usually do not control airway inflammation satisfactorily.

This combination of factors has led to at least 50% of all asthma patients being inadequately treated.

A similar pattern of under-treatment exists in relation to allergic disorders, where drugs are available to treat a number of common conditions but are underused in view of apparent side effects. 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.

Chronic obstructive pulmonary disease (COPD) is a common disease affecting 6% to 8% of the world population. The disease is potentially lethal, and the morbidity and mortality from the condition is considerable. At present, there is no known pharmacological treatment capable of changing the course of COPD.

Other inflammatory disorders which may be mentioned include:

(a) pulmonary fibrosis (this is less common than COPD, but is a serious disorder with a very bad prognosis. No curative treatment exists);

(b) inflammatory bowel disease (a group of disorders with a high morbidity rate. Today only symptomatic treatment of such disorders is available); and

(c) rheumatoid arthritis and osteoarthritis (common disabling inflammatory disorders of the joints. There are currently no curative, and only moderately effective symptomatic, treatments available for the management of such conditions).

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.

For example, 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).

Another class of enzymes that metabolize arachidonic acid are the cyclooxygenases. Arachidonic acid metabolites that are produced by this process include prostaglandins, thromboxanes and prostacyclin, all of which possess physiological or pathophysiological activity. In particular, the prostaglandin PGE₂ 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 PGE₂, 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.

Thus, in general, agents that are capable of blocking the formation of arachidonic acid metabolites are likely to be of benefit in the treatment of inflammation.

Many pharmaceutically active compounds are administered as salts. The solid state properties of a drug, as well as its properties in solution, can be modified by salt formation. In many cases, 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).

The formation of 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.

Prior Art

International patent application WO 00/034269 discloses various compounds including thiourea-containing 1 ,2,3-triazole-4-carboxylic acid amides. This document does not mention or suggest the use of such compounds in the treatment of inflammation.

Hetereoaryl-based compounds including triazoles have been disclosed in several publications. For example, international patent application WO 2005/007625 discloses anti-tuberculosis compounds that include triazoles; international patent application WO 2004/106324 discloses inter alia triazoles for use as herbicides; international patent applications WO 02/070483 and WO 03/016304 disclose various pest-controlling agents that include triazoles; US Patent No. 2002/009116 and international patent application WO 99/32454 disclose inter alia triazoles for use as Factor Xa inhibitors; international patent application WO 01/21160 discloses antiviral compounds that include triazoles. There is no disclosure in any of these documents of 1 (N)-unsubstituted-1 ,2,3- triazole-4-carboxylic acid amides for use in treating inflammation and/or as inhibitors of lipoxygenases.

International patent applications WO 2004/080999, WO 2006/032851 and WO 2006/032852 all disclose various 3-amidopyrazoles for use in the treatment of inflammation. However, there is no disclosure or suggestion in any of these documents of 1 ,2,3-triazole-4-carboxylic acid amides.

International patent application WO 97/30034 discloses various 4- aminoquinazoline derivatives for use as antitumor agents. The document does not disclose or suggest compounds without such a substituent, nor does it mention or suggest the use of such compounds in the treatment of inflammation.

International patent application WO 2004/096795 discloses various heterocycles, including triazoles, as inhibitors of protein tyrosine kinases, international patent application WO 02/092573 discloses various heterocycles for use as inhibitors of inter alia JNK3 protein kinases and international patent application WO 01/55115 discloses various aromatic amides that may be useful as activators of caspases and inducers of apoptosis. Accordingly, the compounds disclosed in these documents may be useful in the treatment of inter alia cancer. There is no disclosure or suggestion in any of these documents of the use of such compounds as inhibitors of lipoxygenases.

International patent application WO 97/19062 discloses various heterocycles for the treatment of skin related diseases and further mentions the use of such compounds in the treatment of various inflammatory diseases. However, there this document does not mention or suggest 3-amido triazoles. JP Patent No. 10195063 discloses various 2-ethynylthiazole derivatives that may be employed as leukotriene antagonists, and may therefore be useful in the treatment of inflammation. However, this document does not mention or suggest compounds without such a substituent.

International patent application WO 2004/041789 discloses various compounds that may be useful as protein kinase inhibitors (and therefore useful in the treatment of inter alia autoimmune diseases). However, there is no specific disclosure of a 1 ,2,3-triazole-4-carboxylic acid amide in this document.

International patent applications WO 03/068767, WO 03/037274, WO 96/18617, WO 2005/009954, WO 2005/009539, WO 2004/108133 and WO 2004/106305 all disclose various compounds, including triazoles, that may be useful in the treatment of inflammation. However, none of these documents specifically disclose 1(N)-unsubstituted 1 ,2,3-triazole-4-carboxylic acid amides.

Finally, international patent application WO 2007/051982 discloses certain 1 (N)- unsubstituted 1 ,2,3-triazole-4-carboxylic acid amide compounds, which inhibit the activity of 15-lipoxygenase. The compounds are thus indicated in the treatment of inflammatory diseases. Although very general information is provided in this unpublished document regarding the formation of salts, no specific information is given in relation to what salts may serve to solve the aforementioned problems.

Disclosure of the Invention

According to a first aspect of the invention there is provided a compound formed by an association between:

(i) a moiety A, which moiety is represented by a compound of formula I,

wherein at least one of X¹ and X² independently represents F, Cl, OCF₃, CF₃, CHF₂Or OCHF₂; and

(ii) a moiety B, which moiety comprises a metal, an organic amine or a basic amino acid,

which compounds are referred to together hereinafter as "the compounds of the invention".

Compounds of the invention are formed by an association between moieties A and B. For the avoidance of doubt therefore, 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

A(m) X B(n) wherein m and n represent numerical values (e.g. integers, such as whole integers) determined by factors such as valency, the degree of ionisation and the like.

Although we have found that it is possible to produce compounds of the invention in forms which are greater than 80% ionic (i.e. in salt form), by "at least partly ionic" we include greater than 20%, preferably greater than 30%, and more preferably greater than 40% ionic. The degree (%) of ionisation may be determined by the skilled person using standard techniques, such as solid state NMR, FT-IR, Raman spectroscopy, X-ray diffraction, differential scanning calorimetry (DSC) and microcalorimetry. In this respect, in use and/or as part of a compound of the invention, moiety A may be in ionised form, in the form of the free acid (i.e. protonated), or both.

For the avoidance of doubt, in moiety A, X¹ and X² independently represent H, F, Cl, OCF₃, CF₃, OCHF₂ or CHF₂, although X¹ and X² both cannot both represent H.

Compounds of formula I that may form moiety A in a compound of the invention are disclosed in international patent application WO 2007/051982.

Preferred compounds of formula I include those in which at least one of X¹ and X² independently represents F, Cl or OCF₃.

More preferred compounds of formula I include:

1 ,2,3-triazole-4-carboxylic acid (2-chloro-4-fluorophenyl)amide;

1 ,2,3-triazole-4-carboxylic acid (4-fluorophenyl)amide;

1 ,2,3-triazole-4-carboxylic acid (2,4-dichlorophenyl)amide;

1 ,2,3-triazole-4-carboxylic acid (4-trifluoromethoxyphenyl)amide; and 1 ,2,3-triazole-4-carboxylic acid 2-chloro-4-(trifluoromethyl)phenylamide.

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-ethylpiperidine, 2-piperidino-ethanol and choline.

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 {entgegen) and Z (zυsammen) 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 exhibit tautomerism. All tautomeric forms 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. In the case of a compound of the invention in the form of a salt, 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.

Compounds of formula I (moiety A) may be prepared by standard techniques, for example:

(i) reaction of 1 ,2,3-triazole-4-carboxylic acid, or a Λ/-protected and/or O- protected (e.g. ester) derivative thereof, with a compound of formula II,

WNH₂ Il

wherein W is a structural fragment as represented by

wherein the squiggly line represents the point of attachment (e.g. to the -NH₂ group in, in this case, the compound of formula II) and X¹ and X² are as hereinbefore defined under coupling conditions, for example at around room temperature or above (e.g. up to 40-180⁰C), optionally in the presence of a suitable base (e.g. sodium hydride, sodium bicarbonate, potassium carbonate, pyrrolidinopyridine, pyridine, triethylamine, tributylamine, trimethylamine, dimethylaminopyridine, diisopropylamine, diisopropylethyl-amine, 1 ,8-diaza- bicyclo[5.4.0]undec-7-ene, sodium hydroxide, Λ/-ethyldiisopropylamine, N- (methylpolystyrene)-4-(methylamino)pyridine, butyllithium (e.g. n-, s- or f-butyl- lithium) or mixtures thereof), an appropriate solvent (e.g. tetrahydrofuran, pyridine, toluene, dichloromethane, chloroform, acetonitrile, dimethylformamide, dimethylsulfoxide, water or triethylamine) and a suitable coupling agent (e.g. 1 ,1 '-carbonyldiimidazole, /V.Λ/'-dicyclohexylcarbodiimide, 1 -(3- dimethylaminopropyl)-3-ethylcarbodiimide (or hydrochloride thereof), /V,/V- disuccinimidyl carbonate, benzotriazol-1 -yloxytris(dimethylamino)-phosphoniurn hexafluorophosphate, 2-(1 /-/-benzotriazol-1 -yl)-1 ,1 , 3, 3-tetramethyluronium hexafluorophosphate, benzo-triazol-1 -yloxytris-pyrrolidinophosphonium hexafluorophosphate, bromo-tris-pyrrolidinophosponium hexafluorophosphate, 2-(1 /-/-benzotriazol-1 -yl)-1 , 1 ,3, 3-tetramethyluronium tetrafluorocarbonate, 1 - cyclohexylcarbodiimide-3-propyloxymethyl polystyrene, O-(7-azabenzotriazol-1 - yl)-/V,Λ/,Λ/^',Λ/^'-tetramethyluronium hexafluorophosphate or O-benzotriazol-1 -yl- /V./V./V./V-tetramethyluronium tetrafluoroborate). Alternatively, 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. This activated intermediate may then be reacted with a compound of formula Il under standard conditions, such as those described above. The skilled person will appreciate that when compounds of formula Il are liquid in nature, they may serve as both solvent and reactant in this reaction. 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);

(ii) reaction of 1 ,2,3-triazole-4-carboxylic acid amide, or a Λ/-protected (e.g. at the triazole nitrogen) derivative thereof, with a compound of formula III, W-L¹ III wherein L¹ represents a suitable leaving group, such as halo (e.g. chloro, bromo and iodo), -OSO₂CF₃, -B(OH)₂, -Sn(R^z)₃ (wherein R^z is C_1-6 alkyl and preferably, methyl or butyl), -Pb(OC(O)CH₃)₃, -Bi(W)₂, -Bi(W)₂(OC(O)CH₃)₂, -Bi(W)₂(OC(O)CFa)₂ or -1(W)(BF₄), 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 Λ/,Λ/-diisopropylamide. Catalysts that may be mentioned include Pd₂(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 9O⁰C) under an inert (e.g. argon) atmosphere;

(iii) reaction of a compound of formula IV,

wherein 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. 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. For example, the reaction may be performed without solvent or in the presence of an appropriate solvent (e.g. water, methanol, ethanol, dimethylformamide, dichloromethane, tetrahydrofuran, dioxane, toluene or mixtures thereof) at about room temperature or above (e.g. between 40 and 80⁰C);

(iv) reaction of triazole, or a protected derivative thereof, with an appropriate base (or a mixtures of bases), such as potassium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, sodium hydride, potassium terf-butoxide or an organolithium base, such as π-BuLi, S-BuLi, NBuLi, lithium diisopropylamide or lithium 2,2,6,6-tetramethylpiperidine (which organolithium base is optionally in the presence of an additive (for example, a lithium co-ordinating agent such as an ether (e.g. dimethoxyethane) or an amine (e.g. tetramethylethylenediamine (TMEDA), (-)sparteine or 1 ,3-dimethyl-3,4,5,6-tetrahydro-2(1 /-/)-pyrimidinone

(DMPU) and the like)) followed by reaction with a compound of formula V,

W-N=C=O V

wherein W is as hereinbefore defined, followed by quenching with a suitable proton source (e.g. water or aqueous, saturated NH₄CI solution). The skilled person will appreciate that 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 -CH₂OC₂H₄Si(CH₃)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. O⁰C to -78°C) under an inert atmosphere followed (as appropriate) by deprotection of the Λ/-protective group under standard conditions (e.g. in the case of the SEM group, employing conditions such as the presence of HCI in ethanol);

(v) reaction of a compound of formula Vl,

with 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. In this case, 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 &

Bauer Chemicals), or may be prepared from propiolic acid and a source of azide ions, for example employing reagents and under conditions such as those described hereinbefore in respect of preparation of compounds of formula I

(process step (iii)).

Compounds of formula Il may be prepared:

(I) by reaction of a compound of formula III, as hereinbefore defined, with ammonia, or preferably with a protected derivative thereof (e.g. benzylamine), under conditions such as those described hereinbefore in respect of preparation of compounds of formula I (process step (H)); or

(II) by reduction of a compound of formula VII,

W-NO₂ VII₁

wherein 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)).

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)). Other 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).

Compounds of formulae III, V and VII are either commercially available, are known in the literature, or may be obtained either by analogy with the processes described herein, or by conventional synthetic procedures, in accordance with standard techniques, from available starting materials using appropriate reagents and reaction conditions. In this respect, the skilled person may refer to inter alia "Comprehensive Organic Synthesis" by B. M. Trost and I. Fleming, Pergamon Press, 1991.

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. In the case where 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 NiCI₂ (for the conversion to a chloro group). In this respect, 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.

It will be appreciated by those skilled in the art that, in the processes described above and hereinafter, the functional groups of intermediate compounds may need to be protected by protecting groups. For example the triazole nitrogen may need to be protected. Suitable nitrogen-protecting groups include those which form:

(i) carbamate groups (i.e. alkoxy- or aryloxy-carbonyl groups);

(ii) amide groups (e.g. acetyl groups);

(iii) /V-alkyl groups (benzyl or SEM groups); (iv) Λ/-sulfonyl groups (e.g. Λ/-arylsulfonyl groups); (v) Λ/-phosphinyl and Λ/-phosphoryl groups (e.g. diarylphosphinyl and diarylphosphoryl groups); or

(vi) Λ/-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 200⁰C.

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.

The type of chemistry involved will dictate the need, and type, of protecting groups as well as the sequence for accomplishing the synthesis.

The use of protecting groups is fully described in "Protective Groups in Organic Chemistry, edited by J W F McOmie, Plenum Press (1973), and "Protective Groups in Organic Synthesis", 3^rd edition, T.W. Greene & P. G. M. Wutz, Wiley- lnterscience (1999).

Compounds of the invention may be obtained in crystalline form by way of a process that comprises crystallising a compound of the invention.

Although 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.

It may be possible to obtain crystalline compounds of the invention via crystallisation advantageously following dissolution and/or suspension of the compound, or, alternatively, from reaction solutions within which a compound has been formed.

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

C_2-4) alkyl alcohols (e.g. methanol, ethanol, isopropanol), aliphatic and aromatic hydrocarbons (e.g. /so-octane, n-heptane, hexane and toluene), dialkyl ketones

(e.g. methyl ethyl ketone and methyl /so-butyl ketone), dialkyl ethers (e.g. di-/so- propyl ether), acetonitrile, tetrahydrofuran, dioxane, dimethylformamide, N- methylpyrrolidone. Mixtures of any of the above-mentioned solvents may be used. Organic solvents may also be admixed with water or aqueous solutions.

Different crystalline forms may have different solubilities in different organic solvents at any given temperature. In this respect, above-mentioned 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).

The skilled person will appreciate that the concentration in solution of the compound that is to be crystallised, and the solvent system that is used, 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. (The term "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.

Further purification of compounds of the invention may be effected using techniques which are well known to those skilled in the art. For example impurities may be removed by way of recrystallisation from an appropriate solvent system, which may include antisolvent or water. Suitable temperatures and times for the recrystallisation depend upon the concentration in solution of the compound to be crystallised, and upon the solvent system which is used.

Pharmaceutical Preparations and Medical Use

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.

The term "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.

The term "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.

Accordingly, 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, iritis, 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. 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.

Compounds of the invention are indicated both in the therapeutic and/or prophylactic treatment of the above-mentioned conditions.

According to a further aspect of the present invention, there is provided 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.

"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.

Such formulations may be prepared in accordance with standard and/or accepted pharmaceutical practice.

According to a further aspect of the invention there is thus provided 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).

According to a further aspect of the invention, there is provided a combination product comprising:

(I) a compound of the invention; and

(II) another therapeutic agent that is useful in the treatment of inflammation, wherein 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).

Thus, there is further provided:

(1 ) 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; and

(2) a kit of parts comprising components:

(a) a pharmaceutical formulation including a compound of the invention in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier; and

(b) 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.

By "bringing into association", we mean that the two components are rendered suitable for administration in conjunction with each other.

Thus, in relation to the process for the preparation of a kit of parts as hereinbefore defined, by bringing the two components "into association with" each other, we include that 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.

Compounds of the invention may be administered at varying doses. Oral, pulmonary and topical dosages may range from between about 0.01 mg/kg¹ 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

(calculated as the amount of free compound of formula I as hereinbefore defined). For e.g. oral administration, the 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). Intravenously, 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. Advantageously, 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.

In any event, 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.

Biological Test

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. In this particular assay, the lipoxygenase was a purified human 15-lipoxygenase and the fatty acid was arachidonic acid. The assay is performed at room temperature (20-22⁰C) and the following are added to each well in a 96-well microtiter plate: a) 35 μl_ phosphate buffered saline (PBS) (pH 7.4); b) inhibitor (i.e. compound) or vehicle (0.5 μl_ DMSO); c) 10 μL of a 10 x concentrated solution of 15-lipoxygenase in PBS. The plates are incubated for 5 minutes at room temperature; d) 5 μL of 0.125 mM arachidonic acid in PBS. The plate is then incubated for 10 minutes at room temperature; e) the enzymatic reaction is terminated by the addition of 100 μL methanol; and f) the amount of 15-hydroperoxy-eicosatetraenoic acid or 15-hydroxy- eicosatetraenoic acid is measured by reverse phase HPLC.

The invention is illustrated by way of the following examples, in which Figures 1 to 3 comprise infrared spectra of the compounds of Examples 4 (and 5), 6 and 9, respectively, and the following abbreviations may be employed: aq. aqueous

DMAP 4-dimethylaminopyridine

DMF dimethylformamide

DMSO dimethylsulfoxide

EtOAc ethyl acetate EtOH ethanol eq equivalents iPrOH isopropanol i PrOAc isopropyl acetate

MeOH methanol

MS mass spectrum

NMR nuclear magnetic resonance

Pd-C palladium on activated carbon

PyBrop bromotripyrrolidinophosphonium hexafluorophosphate rt room temperature

TBTU O-benzotriazol-1-yl-Λ/,Λ/,Λ/^',Λ/^'-tetramethyluronium tetrafluoroborate

THF tetrahydrofuran

Starting materials and chemical reagents specified in the synthesis described below are commercially available from, e.g. Sigma-Aldrich Fine Chemicals.

Unless otherwise stated, one or more tautomeric forms of compounds of the examples described hereinafter may be prepared in situ and/or isolated. All tautomeric forms of compounds of the examples described hereinafter should be considered to be disclosed.

Compounds of formula I

Examples A to D - General Procedure

(a) 1.2,3-Triazole-4-carboxylic acid

A mixture of propiolic acid (1.55 ml_, 1.76 g, 25 mmol), azidotrimethylsilane (8.4 ml_, 7.3 g, 63 mmol) and MeOH (10 ml_) was stirred at 80⁰C for 3 h in a sealed vial. After cooling to rt the solid formed was collected, washed with Et₂O and dried. Yield 2.11 g (74%). 1H NMR (DMSO-CZ₆, 400 MHz) δ 13.30 (br. s, 2H), 8.40 (s, 1 H).

(b) TBTU (1.1 mmol) was added to a mixture of 1 ,2,3-triazole-4-carboxylic acid (113 mg, 1.0 mmol; see step (a) above), diisopropylethylamine (258 mg, 2 mmol) and DMF (1 mL) and the mixture was stirred at rt for 10 min. The relevant arylamine (1.3 mmol) was added and the mixture was stirred at the indicated temperature for the indicated period of time. The mixture was concentrated and water was added. The mixture was extracted with EtOAc and the combined extracts were washed with water, dried (Na₂SO₄) and concentrated. The residue was purified by chromatography (eluent: EtOAc/heptane) to give the title product.

Table 1 - Examples (Ex. A to D)

Table 2 - Physical properties of the compounds of Examples A to D

¹Run in CDCI₃, 400 MHz

Examples E - 1

General Procedure

(a) 1-r2-(Trimethylsilvπethoxymethvn-1.2.3-triazole

NaH (60% suspension in mineral oil, 1.1O g, 28.4 mmol) was added to a mixture of 1 ,2,3-triazole (1.90 g, 27.0 mmol) and THF (30 ml.) and the mixture was stirred at rt for 1 h. The mixture was cooled in an ice bath and 2-(trimethylsilyl)- ethoxymethyl chloride (5.0 g, 30 mmol) was added dropwise. The mixture was allowed to warm to rt and stirred at rt for 18 h. The precipitate was filtered off and the filtrate was concentrated. Et₂O was added to the residue and the mixture was washed with water, dried (Na₂SO₄) and concentrated to give an oil (5.7 g) which according to ¹H NMR, was a mixture of the title product and the isomeric 2-[2-(trimethylsilyl)ethoxymethyl]-1 ,2,3-triazole. The mixture was used in the next step without further purification.

¹H NMR (CDCI₃, 400 MHz) δ 7.76-7.73 (m, 2H), 5.71 (s, 2H), 3.54 (t, 2H)₁ 0.94 (t, 2H), -0.02 (s, 9H).

(b) 3-[2-(Trimethylsilvπethoxymethyl1-1.2.3-triazole-4-carboxylic acid arylamides Butyllithium (1.6 M in hexanes,1.1 ml_, 1.7 mmol) was added dropwise to a solution of 1-[2-(trimethylsilyl)ethoxymethyl]-1 ,2,3-triazole and 2-[2-(trimethylsilyl)ethoxymethyl]-1 ,2,3-triazole (mixture of isomers, see step (a) above, 300 mg, 1.5 mmol) in THF (20 mL) at -20 ⁰C. The mixture was stirred at -20 ⁰C for 30 min and cooled to -78 ⁰C. A solution of the relevant arylisocyanate (2.0 mmol) in THF (5 mL) was added dropwise and the mixture was stirred at -78°C for 2 h, allowed to warm to rt and then stirred at rt for 18 h. Et₂O and NH₄CI (aq, sat,) were added and the layers were separated. The aqueous phase was extracted with Et₂O and the combined extracts were dried (Na₂SO₄) and concentrated. The residue was purified by chromatography (eluent: EtOAc/heptane) to give the sub-title products (Intermediates (b)). (c) 1 ,2,3-Triazole-4-carboxylic acid arylamides

A mixture of the relevant 3-(2-trimethylsilylethoxymethyl)-1 ,2,3-triazole-4- carboxylic acid arylamide (1.0 mmol; see step (b) above) and HCI (2.7 M in EtOH, 1.5 mL) was stirred at rt for 20 min and concentrated. The residue was purified by chromatography (eluent EtOAc/heptane) to give the title products.

Table 3 - Intermediates (b) and Examples (Ex. E to I; (c))

Table 4 - Physical properties of the compounds of Intermediates (b) E to I and Examples (c) E to I

Example J

1 ,2,3-Triazole-4-carboxylic acid 4-trifluoromethoxypheπylamide Butyllithium (1.6 M in hexanes, 900 μL, 1.5 mmol) was added dropwise to a solution of 1-[2-(trimethylsilyl)ethoxymethyl]-1 ,2,3-triazole and 2-[2-(trimethylsilyl)ethoxymethyl]-1 ,2,3-triazole (mixture of isomers, see step (a), Example E-I above, 300 mg, 1.5 mmol) in THF (12 mL) cooled to -50 ⁰C. The mixture was stirred at -50 ⁰C for 30 min, cooled to -78 ⁰C and a solution of 4- trifluoromethoxy-phenylisocyanate (2 mmol) in THF (5 mL) was added dropwise. The mixture was stirred at -78 ⁰C for 30 min, allowed to warm to rt and stirred at rt for 16 h. The mixture was cooled to 0 ⁰C and HCI (10 mL of 0.27M in EtOH, 2.7 mmol) was added. After stirring at 0 ⁰C for 4 h, the mixture was concentrated and the residue purified by chromatography (eluent: EtOAc/heptane) to give the title product. Yield 0.41 mg (10%). M. W. 272.18; MS (M⁺+1 ), m/z 273 1H NMR (DMSO-Cy₆, 400 MHz), δ 15.71 (br. s, 1 H), 10.63 (s, 1 H), 8.55 (s, 1 H), 7.93 (d, 2H), 7.37 (d, 2H).

Example K

Title compounds of examples above were tested in the biological test described above and were found to exhibit the following IC₅₀ values:

Example A: 570 nM

Example B: 76 nM

Example C: 950 nM Example D: 6980 nM Example G: 250 nM

Example H: 530 nM

Example I: 44 nM

Example J: 4450 nM

Compounds of the Invention

Example 1

1.2,3-Triazole-4-carboxylic acid 4-trifluoromethoxyphenylamide potassium salt 1 ,2,3-Triazole-4-carboxylic acid 4-trifluoromethoxyphenylamide (0.6 g) was dissolved in EtOAc (6 mL) at 40 ⁰C. The temperature was allowed to reach rt and KOH (1.2 eq., 1.47 g, 10% MeOH solution) was added. The solution was concentrated until about 2 mL remained. Heptane (6 m!_) and EtOAc (4 mL) was added and the solution was concentrated until about 5 mL remained. The mixture was added to heptane (30 mL) and allowed to stand at rt for 1 h. The solid was filtered off, washed with heptane and dried to give the title compound. Yield 0.58 g.

¹H NMR (DMSO-CZ₆, 300 MHz) δ 9.95 (s, 1 H), 7.98 (d, 2H), 7.76 (s, 1 H), 7.31 (d, 2H)

Example 2

1 ,2.3-Triazole-4-carboxylic acid 4-fluorophenylamide potassium salt 1 ,2,3-Triazole-4-carboxylic acid 4-fluorophenylamide (0.23 g) was suspended in iPrOAc (6 mL). KOH (1.2 eq., 0.75 g, 10% MeOH solution) was added. After a few minutes a precipitate formed and additional KOH (0.1 eq., 0.06 g, 10% MeOH solution) and MeOH (0.5 mL) was added to obtain a solution. The solution was concentrated until about 5 mL remained. iPrOAc (2 mL) was added to give a slurry which was diluted with iPrOAc (3 x 2 mL) and allowed to stand at rt for 1 h. The solid was filtered off, washed with iPrOAc and dried to give the title compound. Yield 0.26 g. 1H NMR (DMSO-CZ₆, 300 MHz) δ 9.74 (s, 1 H), 7.86-7.79 (m, 2H), 7.69 (s, 1 H), 7.11-7.05 (m, 2H)

Example 3

1.2.3-Triazole-4-carboxylic acid 2.4-dichlorophenylamide sodium salt NaOH (1.2 eq., 0.11 g; 50% aq.) was diluted with MeOH (0.5 mL) and added to a mixture of 1 ,2,3-triazole-4-carboxylic acid 2,4-dichlorophenylamide (0.30 g) and MeOH (3.0 mL). The solution was concentrated to about 1 mL. Within a few min, a precipitate formed and EtOH (2 mL) was added. The mixture was heated to about 50 ⁰C whereupon almost all of the precipitate dissolved. The mixture was concentrated to about 2.5 mL, diluted with EtOH (1 mL), filtered and washed with EtOH (0.5 mL) and heptane (1 mL). The solid was collected and dried to give the title compound. Yield 0.16 g.

¹H NMR (DMSO-CZ₆, 300 MHz) δ 9.67 (s, 1 H), 8.48 (d, 1 H), 7.74 (s, 1 H), 7.66 (d,

1 H), 7.40 (dd, 1 H) Example 4

1 ,2.3-Triazole-4-carboxylic acid 2,4-dichlorophenylamide potassium salt KOH (1.1 eq., 0.74 g, 10% MeOH solution) was added to a mixture of 1 ,2,3-triazole-4-carboxylic acid 2,4-dichlorophenylamide (0.3Og) and MeOH (3.0 ml_). After approximately 30 min iPrOH (2 ml.) was added. The mixture was diluted with iPrOH (1 ml_) and allowed to stand at rt for 30 min. The solid was collected, washed with iPrOH (0.5 mL) and dried to give 0.20 g of the title compound. The infrared spectrum is depicted in Figure 1.

Example 5

1 ,2,3-Triazole-4-carboxylic acid 2.4-dichlorophenylamide potassium Salt

1 ,2,3-Triazole-4-carboxylic acid 2,4-dichlorophenylamide (4.9 g, 19 mmol) was suspended in MeOH (35 g). KOH (1.6 g, 23 mmol) in MeOH (15 g) was added. lsopropanol (100 g) was added and the mixture was stirred at rt for 2 h. The solid was collected, washed with isopropanol and dried. Yield: 4.8g (85%). The infrared spectrum is depicted in Figure 1.

Example 6 1.2.3-Triazole-4-carboxylic acid (2,4-dichlorophenyl)amide Calcium Salt

NaOH (1.1 eq., 0.07 g, 50% aq.) was diluted with MeOH (0.5 mL) and added to a mixture of 1,2,3-triazole-4-carboxylic acid 2,4-dichlorophenylamide (0.20 g), water (1.5 mL) and MeOH (0.5 mL). CaCI₂ (0.5 eq., 0.86 g, 5% MeOH solution) was added. The mixture was allowed to stand at rt overnight. The solid was collected, washed with a mixture of water and MeOH (1 :1 , 0.5 mL) and dried to give the title compound. Yield 0.16 g. The infrared spectrum is depicted in Figure 2.

Example 7 1.2,3-Triazole-4-carboxylic acid 2,4-dichlorophenylamide zinc Salt

NaOH (1.1 eq., 0.07 g, 50% aq.) was diluted with MeOH (0.5 mL) and added to a mixture of 1 ,2,3-Triazole-4-carboxylic acid (2,4-dichlorophenyl)amide (0.20 g), water (1.5 mL) and MeOH (0.5 mL). Zinc chloride (0.5 eq., 0.75 g; 7% MeOH solution) was added. The mixture was heated to 50 ⁰C. 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:

1 ,2,3-triazole-4-carboxylic acid 4-trifluoromethoxyphenylamide sodium salt;

1 ,2,3-triazole-4-carboxylic acid 4-trifluoromethoxyphenylamide calcium salt;

1 ,2,3-triazole-4-carboxylic acid 4-trifluoromethoxyphenylamide zinc salt; 1 ,2,3-triazole-4-carboxylic acid 4-fluorophenylamide sodium salt;

1 ,2,3-triazole-4-carboxylic acid 4-fluorophenylamide calcium salt;

1,2,3-triazole-4-carboxylic acid 4-fluorophenylamide zinc salt;

1 ,2,3-triazole-4-carboxylic acid 2-chloro-4-fluorophenylamide sodium salt;

1 ,2,3-triazole-4-carboxylic acid 2-chloro-4-fluorophenylamide potassium salt; 1 ,2,3-triazole-4-carboxylic acid 2-chloro-4-fluorophenylamide calcium salt; and

1 ,2,3-triazole-4-carboxylic acid 2-chloro-4-fluorophenylamide zinc salt.

Example 9

1 ,2,3-Triazole-4-carboxylic acid 2-chloro-4-trifluoromethylphenylamide potassium Salt

KOH (673 μl_ of 10% aq. solution, 1.2 mmol) was added to a mixture of 1 ,2,3-tri- azole-4-carboxylic acid 2-chloro-4-trifluoromethylphenylamide (291 mg, 1.0 mmol) in EtOAc (3.0 ml_). The mixture was stirred for 10 min at rt and concentrated. The residue was mixed with EtOAc (2 ml_) and concentrated. The procedure was repeated 3 times to remove traces of water. EtOAc:heptane (1 :1 , 6 ml_) was added to the residue and the mixture was stirred for 10 min. The precipitate was collected, washed with EtOAciheptane (1 :1 , 2 x 3 mL) and dried. Yield 311 mg (95%). MS (M -H) 289. 1H NMR (DMSO-Cf₆, 500 MHz) δ 9.93 (s, 1 H), 8.74 (d, 1 H), 7.93 (d, 1 H), 7.81 (s, 1 H), 7.73 (dd, 1H). The infrared spectrum is depicted in Figure 3. Example 10

Solubility Experiments

Solid material was added to a glass vial followed by 1 ml_ of water. Duplicate samples of each salt were prepared. Samples were shaken with an orbital shaker (IKA MTS 2/4 digital; 450 rpm) for 24 h at 20 ⁰C. After 24 h, the samples were allowed to stand at rt for 1.5 hours. The samples were centrifuged (3 x

3000 rpm, 15 minutes) and the supernatant analysed by HPLC-UV (HPLC -

Waters 2795; UV detection at 254 nm (Waters 2487)). The following solubilities for the title compounds were obtained: Example 1 - 540 mg/mL

Example 2 - 300 mg/mL

Example 3 - 22 mg/mL

Example 4 - 90 mg/mL

Example 6 - 2 mg/mL

Claims

1. A compound formed by an association between: (i) a compound of formula I,

wherein X¹ and X² independently represent H, F, Cl, OCF₃, CF₃, OCHF₂ or CHF₂, provided that X¹ and X² both are not both H; and (ii) a metal, an organic amine or a basic amino acid.

2. A compound as claimed in Claim 1 , wherein at least one of X¹ and X² independently represents F, Cl or OCF₃.

3. A compound as claimed in Claim 1 or Claim 2, wherein the compound of formula I is 1 ,2,3-triazole-4-carboxylic acid (2-chloro-4-fluorophenyl)amide.

4. A compound as claimed in Claim 1 or Claim 2, wherein the compound of formula I is 1 ,2,3-triazole-4-carboxylic acid (4-fluorophenyl)amide.

5. A compound as claimed in Claim 1 or Claim 2, wherein the compound of formula I is 1 ,2,3-triazole-4-carboxylic acid (2,4-dichlorophenyl)amide.

6. A compound as claimed in Claim 1 or Claim 2, wherein the compound of formula I is 1 ,2,3-triazole-4-carboxylic acid (4-trifluoromethoxyphenyl)amide.

7. A compound as claimed in Claim 1 or Claim 2, wherein the compound of formula I is 1 ,2,3-triazole-4-carboxylic acid 2-chloro-4-(trifluoromethyl)phenyl- amide.

8. A compound as claimed in any one of the preceding claims, wherein the metal is zinc, aluminium, an alkaline earth metal or an alkali metal.

9. A compound as claimed in Claim 8, wherein the alkaline earth metal is magnesium or calcium.

10. A compound as claimed in Claim 8, wherein the alkali metal is sodium.

11. A compound as claimed in Claim 8, wherein the alkali metal is potassium.

12. A compound as claimed in any one of Claims 1 to 7, wherein the organic amine is benethamine, piperazine, ethylenediamine, 1 /-/-imidazole, morpholine, 4-(2-hydroxyethyl)morpholine, triethanolamine, tromethamine, glucamine, N- methylglucamine, dimethylaminoethanol, procaine, ammonia, diethanolamine, 1- (2-hydroxyethyl)pyrrolidine, pyrrolidine, 4-phenylcyclo-hexylamine, 2- aminoethanol, 2-(diethylamino)ethanol, benzathine, diethylamine, triethylamine, hydrabamine, tris(hydroxymethyl)aminomethane, piperidine, ethanolamine, diethanolamine, triethanolamine, benzylamine, p-aminobenzoic acid, 2-diethyl aminoethyl ester, 1-ethylpiperidine, 2-piperidino-ethanol or choline.

13. A compound as claimed in any one of Claims 1 to 7, wherein the basic amino acid is lysine, histadine, a betaine or L-arginine.

14. A compound as claimed in any one of the preceding claims that is in the form of a salt.

15. A compound as defined in any one of Claims 1 to 14 for use as a pharmaceutical.

16. A pharmaceutical formulation including a compound as defined in any one of Claims 1 to 14 in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.

17. A compound as defined in any one of Claims 1 to 14 for use in the treatment of a disease in which inhibition of the activity of a lipoxygenase is desired and/or required.

18. Use of a compound as defined in any one of Claims 1 to 14 for the manufacture of a medicament for the treatment of a disease in which inhibition of the activity of a lipoxygenase is desired and/or required.

19. A compound as claimed in Claim 17, or a use as claimed in Claim 18, wherein the lipoxygenase is 15-lipoxygenase.

20. A compound or use as claimed in any one of Claims 17 to 19 (as appropriate), wherein the disease is inflammation and/or has an inflammatory component.

21. A compound or use as claimed in Claim 20 wherein the disease is asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, an allergic disorder, rhinitis, inflammatory bowel disease, an ulcer, inflammatory pain, fever, atherosclerosis, coronary artery disease, vasculitis, pancreatitis, arthritis, osteoarthritis, rheumatoid arthritis, conjunctivitis, iritis, scleritis, uveitis, a wound, dermatitis, eczema, psoriasis, stroke, diabetes, autoimmune diseases, Alzheimer's disease, multiple sclerosis, sarcoidosis, Hodgkin's disease or another malignancy.

22. A method of treatment of a disease in which inhibition of the activity of a lipoxygenase is desired and/or required, which method comprises administration of a therapeutically effective amount of a compound as defined in any one of Claims 1 to 14 to a patient suffering from, or susceptible to, such a condition.

23. A combination product comprising:

(I) a compound as defined in any one of Claims 1 to 14; and

24. A combination product as claimed in Claim 23 which comprises a pharmaceutical formulation including a compound as defined in any one of Claims 1 to 14, another therapeutic agent that is useful in the treatment of inflammation, and a pharmaceutically-acceptable adjuvant, diluent or carrier.

25. A combination product as claimed in Claim 23 which comprises a kit of parts comprising components:

(a) a pharmaceutical formulation including a compound as defined in any one of Claims 1 to 14 in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier; and

(b) 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.

26. A process for the preparation of a compound as defined in any one of Claims 1 to 14, which comprises bringing into association the compound of formula I with the metal, the organic amine or the basic amino acid.

27. A process as claimed in Claim 26, which further comprises crystallisation of the compound.

28. A process for the preparation of a pharmaceutical formulation as defined in Claim 16, which process comprises bringing into association a compound as defined in any one of Claims 1 to 14 with a pharmaceutically-acceptable adjuvant, diluent or carrier.

29. A process for the preparation of a combination product as defined in any one of Claims 23 to 25, which process comprises bringing into association a compound as defined in any one of Claims 1 to 14 with the other therapeutic agent that is useful in the treatment of inflammation, and at least one pharmaceutically-acceptable adjuvant, diluent or carrier.