WO2008084218A1 - Dérivés de benzazole pour le traitement d'inflammations - Google Patents

Dérivés de benzazole pour le traitement d'inflammations Download PDF

Info

Publication number
WO2008084218A1
WO2008084218A1 PCT/GB2008/000054 GB2008000054W WO2008084218A1 WO 2008084218 A1 WO2008084218 A1 WO 2008084218A1 GB 2008000054 W GB2008000054 W GB 2008000054W WO 2008084218 A1 WO2008084218 A1 WO 2008084218A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
optionally substituted
groups
chloro
alkyl
Prior art date
Application number
PCT/GB2008/000054
Other languages
English (en)
Inventor
Norbert Hauel
Kirsten Arndt
Henri Doods
Klaus Klinder
Roland Pfau
Original Assignee
Boehringer Ingelheim International Gmbh
Biolipox Ab
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Boehringer Ingelheim International Gmbh, Biolipox Ab filed Critical Boehringer Ingelheim International Gmbh
Publication of WO2008084218A1 publication Critical patent/WO2008084218A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

  • This invention relates to novel pharmaceutically-useful compounds, which compounds are useful as inhibitors of enzymes belonging to the membrane- associated proteins in the eicosanoid and glutathione metabolism (MAPEG) family.
  • MAPEG membrane-associated proteins in the eicosanoid and glutathione metabolism
  • Members of the MAPEG family include the microsomal prostaglandin E synthase-1 (mPGES-1), 5-lipoxygenase-activating protein (FLAP), leukotriene C 4 synthase and microsomal glutathione S-transferases (MGSTl, MGST2 and
  • the compounds are of potential utility in the treatment of inflammatory diseases including respiratory diseases.
  • the invention also relates to the use of such compounds as medicaments, to pharmaceutical compositions containing them, and to synthetic routes for their production.
  • Inflammatory diseases -that affect the population include asthma, inflammatory bowel disease, rheumatoid arthritis, osteoarthritis, rhinitis, conjunctivitis and dermatitis.
  • Inflammation is also a common cause of pain. Inflammatory pain may arise for numerous reasons, such as infection, surgery or other trauma. Moreover, several diseases including malignancies and cardiovascular diseases are known to have inflammatory components adding to the symptomatology of the patients. Asthma is a disease of the airways that contains elements of both inflammation and bronchoconstriction. Treatment regimens for asthma are based on the severity of the condition. Mild cases are either untreated or are only treated with inhaled ⁇ -agonists which affect the bronchoconstriction element, whereas patients with more severe asthma typically are treated regularly with inhaled corticosteroids which to a large extent are anti-inflammatory in their nature.
  • COPD chronic obstructive pulmonary disease
  • COX cyclooxygenase
  • COXs metabolise arachidonic acid to the unstable intermediate prostaglandin H 2 (PGH 2 ).
  • PGH 2 is further metabolized to other prostaglandins including PGE 2 , PGF 2U , PGD 2 , prostacyclin and thromboxane A 2 .
  • PGE 2 metabolise arachidonic acid to the unstable intermediate prostaglandin H 2
  • PGD 2 metabolized to other prostaglandins
  • prostacyclin and thromboxane A 2 are known to have pronounced physiological and pathophysiological activity including pro-inflammatory effects.
  • PGE 2 in particular is known to be a strong pro-inflammatory mediator, and is also known to induce fever and pain. Consequently, numerous drugs have been developed with a view to inhibiting the formation of PGE 2 , including "NSAIDs” (non-steroidal antiinflammatory drugs) and “coxibs” (selective COX-2 inhibitors). These drugs act predominantly by inhibition of COX-I and/or COX-2, thereby reducing the formation of PGE 2 .
  • the inhibition of COXs has the disadvantage that it results in the reduction of the formation of all metabolites downstream of PGH 2 , some of which are known to have beneficial properties, hi view of this, drugs which act by inhibition of COXs are therefore known/suspected to cause adverse biological effects.
  • the non-selective inhibition of COXs by NSAIDs may give rise to gastrointestinal side-effects and affect platelet and renal function.
  • Even the selective inhibition of COX-2 by coxibs, whilst reducing such gastrointestinal side-effects, is believed to give rise to cardiovascular problems.
  • PGH 2 may be transformed to PGE 2 by prostaglandin E synthases (PGES).
  • PGES prostaglandin E synthases
  • mPGES-1 and mPGES-2 microsomal prostaglandin E synthases
  • cPGES cytosolic prostaglandin E synthase
  • the leukotrienes are formed from arachidonic acid by a set of enzymes distinct from those in the COX / PGES pathway.
  • Leukotriene B 4 is known to be a strong proinflammatory mediator, while the cysteinyl-containing leukotrienes C 4 , D 4 and E 4 (CysLTs) are mainly very potent bronchoconstrictors and have thus been implicated in the pathobiology of asthma.
  • the biological activities of the CysLTs are mediated through two receptors designated CysLTi and CysLT 2 .
  • leukotriene receptor antagonists LTRas
  • These drugs may be given orally, but do not control inflammation satisfactorily.
  • the presently used LTRas are highly selective for CySLT 1 . It may be hypothesised that better control of asthma, and possibly also COPD, may be attained if the activity of both of the CysLT receptors could be reduced. This may be achieved by developing unselective LTRas, but also by inhibiting the activity of proteins, e.g. enzymes, involved in the synthesis of the CysLTs. Among these proteins, 5-lipoxygenase, 5-lipoxygenase-activating protein (FLAP), and leukotriene C 4 synthase may be mentioned. A FLAP inhibitor would also decrease the formation of the proinflammatory LTB 4 .
  • mPGES-1, FLAP and leukotriene C 4 synthase belong to the membrane-associated proteins in the eicosanoid and glutathione metabolism (MAPEG) family.
  • Other members of this family include the microsomal glutathione S-transferases (MGSTl, MGST2 and MGST3).
  • MGSTl, MGST2 and MGST3 microsomal glutathione S-transferases
  • compounds prepared as antagonists- to one of the MAPEGs may also exhibit inhibitory activity towards other family members, c.f. J. H Hutchinson et al in J. Med. Chem. 38, 4538 (1995) and D.
  • agents that are capable of inhibiting the action of mPGES-1, and thus reducing the formation of the specific arachidonic acid metabolite PGE 2 are likely to be of benefit in the treatment of inflammation. Further, agents that are capable of inhibiting the action of the proteins involved in the synthesis of the leukotrienes are also likely to be of benefit in the treatment of asthma and COPD.
  • the R , 10 group is attached to either one of the two requisite nitrogen atoms; the dotted line between the nitrogen attached to R , 10 and the carbon atom (bearing the phenyl ring that is substituted by R 11 to R 15 ) represents a single bond; and
  • X represents -O-, -S- or -NR 16 -;
  • R 1 to R 8 and R 11 to R 15 independently represent hydrogen, Ci -6 alkyl (optionally substituted by one or more A 1 groups), C 3-7 cycloalkyl (optionally substituted by one or more A 2 groups), halo, pseudohalo, -OH, -OC 1-4 alkyl (optionally substituted by one or more A 3 groups), -C(O)OH, -C(O)OC M alkyl (optionally substituted by one or more A 4 groups), -C0NR x R y , -SO 2 NR 21 R 22 , -NR 25 C(O)R 26 or -NR 27 SO 2 R 28 ; or any two adjacent substituents (from R 1 to R 4 , R 5 to R 8 and R 11 to R 15 ) may be linked together to form, along with the carbon atoms of the benzene ring to which the two substituents are necessarily attached, a further 5- to 6-membered ring, which ring optionally contains 1 to 3 heteroatoms (such as
  • R 9 represents hydrogen, C 1-5 alkyl (optionally substituted by one or more A 6 groups), C 3-6 cycloalkyl (optionally substituted by one or more A 7 groups),
  • R 10 and R 16 independently represent hydrogen, Cj -5 alkyl (optionally substituted by one or more A 9 groups), C 3-6 cycloalkyl (optionally substituted by one or more A 10 groups) or heterocycloalkyl (optionally substituted by one or more A 11 groups);
  • a 1 to A 11 independently represent halo, pseudohalo, -NR z9 R z10 , -OH, -OC 1-4 alkyl (optionally substituted by one or more halo groups), aryl or heteroaryl (which latter two groups are optionally substituted by halo or C 1-3 alkyl);
  • R z8 represents B 1 ;
  • salts include acid addition salts and base addition salts.
  • Such salts may be formed by conventional means, for example by reaction of a free acid or a free base form of a compound of formula I with one or more equivalents of an appropriate acid or base, 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 the invention in the form of a salt with another counter-ion, for example using a suitable ion exchange resin.
  • Compounds of the invention may contain double bonds and may thus exist as E (entgege ⁇ ) and Z (zusamme ⁇ ) geometric isomers about each individual double bond. All such isomers and mixtures thereof are included within the scope of the invention.
  • R 16 may be attached to either one of the two nitrogen atoms in the requisite imidazole system (and the double bond may be between either nitrogen atom and the carbon atom that is attached to the phenyl ring bearing the R 5 to R 8 substituents).
  • Compounds of the invention may also contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereoisomerism.
  • Diastereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation.
  • the various stereoisomers may be isolated by separation of a racemic or other mixture of the compounds using conventional, e.g. fractional crystallisation or HPLC, techniques.
  • the desired optical isomers may be made by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation or epimerisation (i.e.
  • a 'chiral pool' method by reaction of the appropriate starting material with a 'chiral auxiliary' which can subsequently be removed at a suitable stage, by derivatisation (i.e. a resolution, including a dynamic resolution), for example with a homochiral acid followed by separation of the diastereomeric derivatives by conventional means such as chromatography, or by reaction with an appropriate chiral reagent or chiral catalyst all under conditions known to the skilled person. All stereoisomers and mixtures thereof are included within the scope of the invention.
  • C 1-q alkyl (where q is the upper limit of the range) defined herein may be straight-chain or, when there is a sufficient number (i.e. a minimum of three) of carbon atoms, be branched-chain. Further, when there is a sufficient number (i.e. a minimum of four) of carbon atoms, such groups may also be part cyclic (so forming, for example, a cyclopropylmethylene group). Such alkyl groups may also be saturated or, when there is a sufficient number (i.e. a minimum of two) of carbon atoms, be unsaturated (forming, for example, a C 2-q alkenyl or a C 2-q alkynyl group).
  • C 3-q cycloalkyl groups may be monocyclic or bicyclic non-aromatic alkyl groups, which cycloalkyl groups may further be bridged (so forming, for example, fused ring systems). Such cycloalkyl groups may be saturated or unsaturated, e.g. containing one or more double bond (forming for example a C 3-q cycloalkenyl).
  • C 3-7 cycloalkyl groups that may be mentioned include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl and cycloheptenyl.
  • Optional substituents may be attached at any point on the cycloalkyl group.
  • halo when used herein, includes fluoro, chloro, bromo and iodo (and is preferably fluoro, chloro or bromo).
  • Preferred pseudohalo groups include -CN groups.
  • bicyclic when employed in the context of cycloalkyl, refers to such groups in which the second ring is formed between two adjacent atoms of the first ring (i.e. systems of two rings share one bond formed with two adjacent carbon atoms).
  • bridged when employed in the context of cycloalkyl groups refers to monocyclic or bicyclic groups in which two non- adjacent atoms are linked by an alkylene chain.
  • Aryl groups that may be mentioned include C 6-M (such as C 6-J3 (e.g. C 6-10 )) aryl groups. Such groups may be monocyclic, bicyclic or tricyclic in which at least one ring is aromatic.
  • C ⁇ - ⁇ aryl groups include phenyl, naphthyl and the like, such as 1,2,3,4-tetrahydronaphthyl, indanyl, indenyl and fluorenyl.
  • the point of attachment of aryl groups may be via any atom of the ring system. However, when aryl groups are bicyclic or tricyclic, they are linked to the rest of the molecule via an aromatic ring.
  • Heteroaryl groups that may be mentioned include those which have between 5 and
  • Such groups may be monocyclic, bicyclic or tricyclic, provided that at least one of the rings is aromatic and wherein at least one (e.g. one to four) of the atoms in the ring system is other than carbon (i.e. a heteroatom).
  • Heteroaryl groups that may be mentioned include acridinyl, benzimidazolyl, benzodioxanyl, benzodioxepinyl, benzodioxolyl (including 1,3-benzodioxolyl), benzofuranyl, benzofurazanyl, benzothiadiazolyl (including 2,1,3- benzothiadiazolyl), benzothiazolyl, benzoxadiazolyl (including 2,1,3- benzoxadiazolyl), benzoxazinyl (including 3,4-dihydro-2H-l,4-benzoxazinyl), benzoxazolyl, benzomorpholinyl, benzothienyl, carbazolyl, chromanyl, cinnolinyl, furanyl, imidazolyl, imidazo[l,2- ⁇ ]pyridyl, indazolyl, indolinyl, indolyl, isobenzofuranyl
  • heteroaryl groups may, where appropriate, be located on any atom in the ring system including a heteroatom.
  • the point of attachment of heteroaryl groups may be via any atom in the ring system including (where appropriate) a heteroatom (such as a nitrogen atom), or an atom on any fused carbocyclic ring that may be present as part of the ring system.
  • heteroaryl groups when heteroaryl groups are bicyclic or tricyclic, they are attached to the rest of the molecule via an aromatic ring.
  • Heteroaryl groups may also be in the JV- or S- oxidised form.
  • Heterocycloalkyl groups that may be mentioned include non-aromatic monocyclic and bicyclic heterocycloalkyl groups (which groups may further be bridged) in which at least one (e.g. one to four) of the atoms in the ring system is other than carbon (i.e. a heteroatom), and in which the total number of atoms in the ring system is between three and twelve (e.g. between five and ten). Further, such heterocycloalkyl groups may be saturated or unsaturated containing one or more double and/or triple bonds, forming for example a C 2-q heterocycloalkenyl (where q is the upper limit of the range) or a C 7-q heterocycloalkynyl group.
  • C 2-q heterocycloalkyl groups that may be mentioned include 7-azabicyclo- [2.2.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl, 6-azabicyclo[3.2.1]-octanyl, 8- azabicyclo[3.2.1]octanyl, aziridinyl, azetidinyl, dihydropyranyl, dihydropyridyl, dihydropyrrolyl (including 2,5-dihydropyrrolyl), dioxolanyl (including 1,3- dioxolanyl), dioxanyl (including 1,3-dioxanyl and 1 ,4-dioxanyl), dithianyl (including 1 ,4-dithianyl), dithiolanyl (including 1,3-dithiolanyl), imidazolidinyl, imidazolinyl, morpholinyl, 7-oxabicyclo[2.2.1]heptanyl, 6-
  • Substituents on heterocycloalkyl groups may, where appropriate, be located on any atom in the ring system including a heteroatom. Further, in the case where the substituent is another cyclic compound, then the cyclic compound may be attached through a single atom on the heterocycloalkyl group, forming a so-called "spiro"- compound.
  • the point of attachment of heterocycloalkyl groups may be via any atom in the ring system including (where appropriate) a heteroatom (such as a nitrogen atom), or an atom on any fused carbocyclic ring that may be present as part of the ring system.
  • Heterocycloalkyl groups may also be in the N- or S- oxidised form.
  • Heteroatoms that may be mentioned include phosphorus, silicon and, preferably, oxygen, nitrogen and sulphur.
  • R 1 represents -SO 2 NR 21 R 22 and R 2 represents -NR z5 C(O)R z6 , in which R zl , R 22 , R z5 and R z6 all represent B 1 , then those B 1 groups may be the same or different.
  • R 10 and R 16 independently represent hydrogen, Ci -5 alkyl (optionally substituted by one or more A 9 groups) or C 3-6 cycloalkyl (optionally substituted by one or more A 10 groups).
  • Preferred compounds of the invention include those in which, when any one of R to R 8 and R 11 to R 15 represents: optionally substituted Ci -6 alkyl, they preferably represent Ci -3 (e.g. C 1-2 ) alkyl optionally substituted by one or more A 1 (e.g.
  • fluoro groups (so forming, for example, a -CF 3 , -CHF 2 , -CH 2 F or -CH 2 CF 3 group); optionally substituted -OCj -4 alkyl, they preferably represent -OCi -3 (e g-
  • a 3 e.g. fluoro
  • a 3 e.g. fluoro
  • R x and R y independently represent H or B 1 , in which B 1 preferably represents optionally substituted Cj -4 alkyl (hence, -C(0)NR x R y may represent -C(O)NH 2 , -C(O)N(H)Ci -4 alkyl or -C(O)N(CM alkyl) 2 ); -SO 2 NR 21 R 22 , then R zl and R 22 independently represent H or B 1 , in which B 1 preferably represents optionally substituted Ci -4 alkyl (hence, -SO 2 NR 21 R may represent -SO 2 NH 2 , -SO 2 N(H)Cj -4 alkyl or -SO 2 N(Ci -4 alkyl) 2 ).
  • More preferred compounds of the invention include those in which when R 9 represents: optionally substituted Ci -5 alkyl, it preferably represents C 1-3 (e.g. C 1-2 ) alkyl (e.g. -CH 2 -CH 3 or, preferably, -CH 3 ) optionally substituted by one or more A 6 (e.g. fluoro) groups (so forming for example a -CF 3 , -CHF 2 , -CH 2 F or -CH 2 CF 3 group); optionally substituted -OCj -4 alkyl, it preferably represents -OCj -3 (e.g. -OCi -2 ) alkyl optionally substituted by one or more A 8 (e.g. fluoro) groups (so forming, for example a -OCF 3 group).
  • a 6 e.g. fluoro
  • -OCj -4 alkyl it preferably represents -OCj -3 (e.g. -OCi -2 ) alkyl optional
  • More preferred compounds of the invention include those in which when either of R 10 or R 16 represent optionally substituted C ⁇ 5 alkyl, then they preferably represent Ci -4 (e.g. Ci -2 ) alkyl optionally substituted by one or more A 9 groups, in which A 9 is pseudohalo or, preferably, halo (e.g. fluoro) or -OCi -4 alkyl optionally substituted by one or more fluoro atoms (hence, when such Cj -5 alkyl groups are substituted, they are preferably -CH 2 CH 2 F, -CH 2 CF 3 or -CH 2 CH 2 -O-Ci -4 alkyl).
  • R 5 to R 8 independently represent hydrogen, Ci -5 alkyl (optionally substituted by one or more A 1 groups), C 3-6 cycloalkyl (optionally substituted by one or more A 2 groups, but preferably unsubstituted), halo, pseudohalo or -OC 1-4 alkyl (optionally substituted by one or more A 3 groups);
  • R 10 and R 16 independently represent heterocycloalkyl (optionally substituted by one or more A 11 groups, but which is preferably unsubstituted) or, preferably, hydrogen, C 1-5 alkyl (optionally substituted by one or more A 9 groups) or C 3-6 cycloalkyl (optionally substituted by one or more A 10 groups, but which is preferably unsubstituted); when R 10 and/or R 16 represent heterocycloalkyl, then it is preferably a five to eight-membered (e.g.
  • a 1 to A 11 independently represent aryl or heteroaryl (optionally substituted as defined herein), -NR z9 R zl ° or, preferably, pseudohalo or, more preferably, -OC 1-4 alkyl (optionally substituted by one or more halo groups) or, even more preferably, halo (e.g. fluoro); when R 5 to R 9 represent substituted Ci -5 alkyl groups, they are preferably substituted Cj -3 (e.g.
  • Cj -2 alkyl groups (such as -CF 3 , -CHF 2 , -CH 2 F or, e.g. in the case of R 9 , -CH 2 CF 3 ); when R 5 to R 9 represent substituted -OC 1-4 alkyl groups, they are preferably substituted -OC 1-3 (e.g. -OC 1-2 ) alkyl groups (such as -OCF 3 ); when R 10 or R 16 represent optionally substituted Ci -5 alkyl groups, they may be unsubstituted Cj -4 (e.g. C 1-3 ) alkyl groups, or, preferably, substituted C 1-3 (e.g.
  • R x and R y , R zl and R 22 or R z9 and R zl ° are linked, they preferably form a saturated 5-, 6- or 7-membered (e.g. 5- or 6-membered) ring, which ring optionally contains a further nitrogen or oxygen heteroatom and is optionally substituted as defined herein;
  • R x and R y , R zl and R 22 and R z9 and R zl ° are preferably not linked together to form a ring;
  • B 1 and B 2 independently represent Ci -4 (e.g. Ci -3 ) alkyl optionally substituted by one or more fluoro atoms. More preferred compounds of the invention include those in which:
  • R 1 to R 4 and R 11 to R 15 independently represent hydrogen, C] -4 alkyl (optionally substituted by one or more A 1 groups), C 3-5 cycloalkyl (optionally substituted by one or more A 2 groups, but preferably unsubstituted), halo (e.g. iodo or, preferably, fluoro, chloro or bromo), pseudohalo (e.g. -CN), or -OC M alkyl
  • any two adjacent substituents may be linked together as hereinbefore defined (e.g. to form a 5- or 6- membered ring optionally containing one nitrogen or oxygen heteroatom, which ring is optionally substituted by one substituent selected from A 5 ; hence such rings may be unsubstituted carbocyclic rings);
  • R 5 to R 8 independently represent hydrogen, halo (e.g. fluoro, chloro or bromo) or Cj -3 (e.g. Ci -2 ) alkyl (e.g. methyl) optionally substituted by one or more A 1 groups (so forming, for example, a -CF 3 group);
  • R 9 represents hydrogen, C 1-5 (e.g. C 1-4 ) alkyl (e.g. methyl) optionally substituted by one or more A 6 groups (so forming, for example, a -CF 3 group), C 3-6 cycloalkyl (optionally substituted by one or more A 7 groups, but preferably unsubstituted) or halo (e.g. fluoro, chloro, bromo or iodo);
  • R 10 and R 16 independently represent heterocycloalkyl, such as a five or six- membered monocyclic heterocycloalkyl group (optionally substituted by one or more A 11 groups, but preferably, unsubstituted) or, preferably, hydrogen, C 1 -S (e.g.
  • C 1-4 ) alkyl e.g. butyl, methyl or, preferably, ethyl
  • a 9 groups forming, for example, a -CH 2 CH 2 -OCH 3 group or, preferably, a -CH 2 CH 2 F or a -CH 2 CF 3 group
  • C 3-6 cycloalkyl optionally substituted by one or more A 10 groups, but preferably unsubstituted
  • a 1 to A 11 independently represent aryl (e.g. phenyl), heteroaryl (which latter two groups are optionally substituted by halo or Ci -3 alkyl), -NR z9 R z , -OC 1-4 (e.g. -OCi -2 ) alkyl (optionally substituted by one or more halo atoms) or, preferably, halo (e.g. fluoro).
  • Preferred aryl and heteroaryl groups that A 1 to A 11 (when they represent such groups) may represent include optionally substituted phenyl, naphthyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl (e.g 1-imidazolyl, 2-imidazolyl or A- imidazolyl), oxazolyl, isoxazolyl, thiazolyl, pyridyl (e.g.
  • Preferred phenyl rings that the phenyl ring of formula I containing the substituents R 11 to R 15 may represent include those in which the phenyl ring is substituted with one or two substituents (preferably one of which is located in the position oriho to the point of attachment with the imidazole ring of formula I, and, if present, the second substituent is located in the other ortho position; i.e. those positions represented by R 11 and R 15 in the compound of formula I) preferably selected from C 1-3 (e.g. C 1-2 ) alkyl (e.g. methyl) or, more preferably, halo (e.g. fluoro or chloro).
  • substituents preferably one of which is located in the position oriho to the point of attachment with the imidazole ring of formula I, and, if present, the second substituent is located in the other ortho position; i.e. those positions represented by R 11 and R 15 in the compound of formula I
  • C 1-3 e.g. C
  • such phenyl groups preferably include 2,6-dimethylphenyl or, more preferably, 2-chloro-6-fiuorophenyl and 2-chlorophenyl.
  • Preferred benzazole rings of compounds of formula I include those that are unsubstituted at the benzenoid moiety of the benzazole bicycle or optionally substituted (e.g. with two or, preferably, one substituent), for example at the 5-, 6- or 7-position of the benzazole ring, with a substituent selected from halo (e.g. chloro, fluoro or iodo) or Ci -3 (e.g. Ci -2 ) alkyl (e.g. methyl), which alkyl group is optionally substituted by one or more halo (e.g. fluoro) atoms (so forming, for example, a -CF 3 group).
  • halo e.g. chloro, fluoro or iodo
  • Ci -3 e.g. Ci -2
  • alkyl e.g. methyl
  • alkyl group is optionally substituted by one or more halo (e.g. fluoro) atom
  • Such benzazole groups include unsubstituted benzoimidazole, l(N)-methylbenzoimidazole, 5- chlorobenzoimidazole, l(N)-methyl-5-chlorobenzoimidazole, 5-fluorobenzo- imidazole, 1 (N)-w-butylbenzoimidazole, 1 (N)-methyl-6-chlorobenzoimidazole,
  • More preferred compounds include those in which: X represents -S-, preferably, -O- or, more preferably, -NR 1 -; R 1 , R 6 , R 8 , R 10 , R 12 , R 13 and R 14 independently represent hydrogen; R 5 and R 7 independently represent halo (e.g. chloro) or, more preferably, hydrogen; one of R 5 and R 7 represents halo (e.g. chloro) or, preferably, hydrogen, and the other represents hydrogen;
  • R 2 represents C 1-2 alkyl (e.g. methyl) optionally substituted by A 1 (so forming, for example when A 1 represents fluoro, a trifluoromethyl group) or, preferably, hydrogen or halo (e.g. iodo, preferably, fluoro or, more preferably, chloro);
  • R 3 represents C 1-2 alkyl (e.g. methyl), optionally substituted by A 1 (but preferably unsubstituted), or R 3 represents halo (e.g. chloro) or, more preferably, hydrogen; R 4 represents halo (e.g. iodo or, preferably, chloro) or, more preferably, hydrogen; R 9 represents C 1-3 (e.g. C 1-2 ) alkyl (e.g. methyl) or, preferably, hydrogen or halo (e.g. chloro or, preferably, bromo);
  • R 10 represents C 1-2 alkyl (e.g. methyl) optionally substituted by A 9 (but preferably unsubstituted) or, more preferably, R 10 represents hydrogen;
  • R 11 and R 15 independently represent C 1-3 (e.g. C 1-2 ) alkyl (e.g. methyl) or, preferably, hydrogen or, more preferably halo (e.g. fluoro or chloro); either one of R 11 and R 15 represents C 1-3 (e.g. Ci -2 ) alkyl (e.g. methyl) or, preferably, halo (e.g. fluoro or chloro) and the other represents C 1-3 (e.g. Ci -2 ) alkyl (e.g. methyl), preferably, hydrogen or, more preferably, halo (e.g. fluoro or chloro);
  • R 16 represents a 5- or 6-membered heterocycloalkyl group (e.g. tetrahydro- pyranyl), C 3-6 cycloalkyl (e.g. cyclopropyl or cyclohexyl) or, more preferably, hydrogen or Ci -5 (e.g. Ci -4 ) alkyl (preferably Ci -3 (e.g. C 1-2 ) alkyl), for example 1- ethylpropyl (i.e. branched alkyl), ethyl, propyl, preferably, butyl (e.g. n-butyl) or, more preferably, methyl, and which alkyl group may be substituted (e.g. by one A 9 substituent), but is preferably unsubstituted;
  • C 3-6 cycloalkyl e.g. cyclopropyl or cyclohexyl
  • Ci -5 e.g. Ci -4 alkyl
  • Ci -3 e.
  • a 1 to A 11 represent(s) aryl (e.g. phenyl), -NR z9 R z10 or -OC 1-3 alkyl (e.g. -OCi -2 alkyl) optionally substituted by one or more halo (e.g. fluoro) atoms (so forming e.g. -OCF 3 );
  • R z9 and R zl ° independently represent B 1 ;
  • B 1 represents C 1-3 alkyl (e.g. methyl).
  • Particularly preferred compounds of the invention include those of the examples described hereinafter.
  • a reagent e.g. an acid
  • Such conditions include reaction in the presence of a reagent such as P 2 O 5 or an acid (such as concentrated acetic acid or a sulfonic acid (e.g. para-toluene sulfonic acid monohydrate)) at room or, preferably, elevated temperature (e.g. at reflux);
  • R ⁇ represents either R 10 or R 16 (as appropriate) provided that it does not represent hydrogen
  • L 1 represents a suitable leaving group, such as chloro, bromo, iodo or a sulfonate group (e.g. -OS(O) 2 CF 3 , -OS(O) 2 CH 3 , -OS(O) 2 PbMe or a nonaflate)
  • R 10 and R 16 are as hereinbefore defined, under standard reaction conditions known to those skilled in the art, for example at around room temperature or above (e.g. up to 60-70 0 C) in the presence of a suitable base (e.g.
  • pyrrolidinopyridine pyridine, triethylamine, tributylamine, trimethylamine, dimethylaminopyridine, diisopropylamine, 1 ,8-diazabicyclo[5.4.0]undec-7-ene, sodium hydroxide, sodium hydride, t-BuOK or mixtures thereof
  • an appropriate solvent e.g. pyridine, dichloromethane, chloroform, tetrahydrofiiran, dimethylformamide, triethylamine, dimethylsulfoxide, water or mixtures thereof
  • a phase transfer catalyst e.g. pyridine, dichloromethane, chloroform, tetrahydrofiiran, dimethylformamide, triethylamine, dimethylsulfoxide, water or mixtures thereof
  • halogenating agent e.g. for introduction of a bromo group, bromine, 1,2- dibromotetrachloroethane or, preferably, N-bromosuccinimide, or, for the introduction of a chloro group, chlorine, iodine monochloride or, preferably, JV- chlorosuccinimide
  • a radical initiator e.g. AIBN
  • a suitable solvent e.g. in the case of a radical reaction, in the presence of tetrachloromethane.
  • suitable solvent e.g. in the case of a radical reaction, in the presence of tetrachloromethane.
  • halogenating agents include iodine and diiodoethane (for iodine atoms), and fluorine and CF 3 OF (for fluorine atoms); and
  • L 2 represents a suitable leaving group, such as iodo, chloro or, especially, bromo, and X and R 1 to R 8 are as hereinbefore defined, with a compound of formula VI,
  • R 11 to R 15 are as hereinbefore defined, under cyclisation conditions known to those skilled in the art, for example optionally in the presence of an appropriate base such as one described hereinbefore in respect of process step (ii) above, or another suitable base such as NaH, ⁇ yV-dime ⁇ ylethylenediam ⁇ ne, Na 2 CO 3 , K 2 CO 3 , KHCO 3 , K 3 PO 4 , Cs 2 CO 3 , t-BuONa or /-BuOK (or a mixture thereof; preferred bases include KHCO 3 ) and a suitable solvent such as dichloromethane, dioxane, toluene, ethanol, isopropanol, dimethylformamide, ethylene glycol, ethylene glycol dimethyl ether, water, dimethylsulfoxide, acetonitrile, dimethylacetamide, 7V-methylpyrrolidinone, tetrahydrofuran (or a mixture thereof; preferred solvents include THF and water) at room temperature
  • X and R 1 to R 4 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. sodium hydride, sodium bicarbonate, potassium carbonate, pyrrolidinopyridine, pyridine, triethylamine, tributylamine, trimethylamine, dimethylarninopyridine, diisopropylamine, diisopropylethylamine, l,8-diazabicyclo[5.4.0]undec-7-ene, sodium hydroxide, N- ethyldiisopropylamine, iV-(methylpolystyrene)-4-(methylamino)pyridine, butyllithium (e.g.
  • an appropriate solvent e.g. tetrahydrofuran, pyridine, toluene, xylene, dichloromethane, chloroform, acetonitrile, dimethylformamide, dimethylsulfoxide or water, or mixtures thereof
  • a suitable coupling agent e.g.
  • the compound of formula VII 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
  • Compounds of formula V may be prepared by reaction of a compound corresponding to a compound of formula V but in which L 2 represents hydrogen, with a halogen source (such as one described hereinbefore in respect of preparation of compounds of formula I (process step (Ui))), under standard reaction conditions, for example in the presence of mildly acidic conditions (e.g. in the presence of acetic acid).
  • a halogen source such as one described hereinbefore in respect of preparation of compounds of formula I (process step (Ui)
  • mildly acidic conditions e.g. in the presence of acetic acid
  • the substituents R 1 to R 15 in final compounds of the invention or relevant intermediates may be modified one or more times, after or during the processes described above by way of methods that are well known to those skilled in the art. Examples of such methods include substitutions, reductions, oxidations, alkylations, acylations, hydrolyses, esterifications, 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. For example, in cases where R 1 represents -C(O)OCj -4 alkyl (i.e.
  • Compounds of the invention may be isolated from their reaction mixtures using conventional techniques.
  • 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.
  • a compound of the invention for use as a pharmaceutical.
  • compounds of the invention may possess pharmacological activity as such, certain pharmaceutically-acceptable (e.g. "protected") derivatives of compounds of the invention may exist or be prepared which may not possess such activity, but may be administered parenterally or orally and thereafter be metabolised in the body to form compounds of the invention.
  • Such compounds (which may possess some pharmacological activity, provided that such activity is appreciably lower than that of the "active" compounds to which they are metabolised) may therefore be described as "prodrugs" of compounds of the invention.
  • prodrug of a compound of the invention we include compounds that form a compound of the invention, in an experimentally-detectable amount, within a predetermined time (e.g. about 1 hour), following oral or parenteral administration. All prodrugs of the compounds of the invention are included within the scope of the invention.
  • certain compounds of the invention may possess no or minimal pharmacological activity as such, but may be administered parenterally or orally, and thereafter be metabolised in the body to form compounds (e.g. compounds of the invention) that possess pharmacological activity as such (including, but not limited to, corresponding compounds of formula I, in which R 1 to R 8 or R 11 to R 15 represents -C(O)OH).
  • compounds e.g. compounds of the invention
  • Such compounds which also includes compounds that may possess some pharmacological activity, but that activity is appreciably lower than that of the "active" compounds of the invention to which they are metabolised), may also be described as "prodrugs".
  • the compounds of the invention are useful because they possess pharmacological activity, and/or are metabolised in the body following oral or parenteral administration to form compounds which possess pharmacological activity (e.g. similar or pronounced pharmacological activity as compared to the compounds of the invention from which they are formed).
  • Compounds of the invention are particularly useful because they may inhibit the activity of a member of the MAPEG family.
  • Compounds of the invention are particularly useful because they may inhibit (for example selectively) the activity of prostaglandin E synthases (and particularly microsomal prostaglandin E synthase- 1 (mPGES-1)), i.e. they prevent the action of mPGES-1 or a complex of which the mPGES-1 enzyme forms a part, and/or may elicit a mPGES-1 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 PGES, and particularly mPGES-1, 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, pain generally and/or fever.
  • compounds of the invention may be useful in the treatment of asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, inflammatory bowel disease, irritable bowel syndrome, inflammatory pain, fever, migraine, headache, low back pain, fibromyalgia, myofascial disorders, viral infections ⁇ e.g. influenza, common cold, herpes zoster, hepatitis C and AIDS), bacterial infections, fungal infections, dysmenorrhea, burns, surgical or dental procedures, malignancies ⁇ e.g.
  • hyperprostaglandin E syndrome classic Bartter syndrome, atherosclerosis, gout, arthritis, osteoarthritis, juvenile arthritis, rheumatoid arthritis, rheumatic fever, ankylosing spondylitis, Hodgkin's disease, systemic lupus erythematosus, vasculitis, pancreatitis, nephritis, bursitis, conjunctivitis, ulceris, scleritis, uveitis, wound healing, dermatitis, eczema, psoriasis, stroke, diabetes mellitus, neurodegenerative disorders such as Alzheimer's disease and multiple sclerosis, autoimmune diseases, allergic disorders, rhinitis, ulcers, coronary heart disease, sarcoidosis and any other disease with an inflammatory component.
  • Compounds of the invention may also have effects 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 member of the MAPEG family such as a PGES (e.g. mPGES- 1), LTC 4 synthase and/or FLAP and/or a method of treatment of a disease in which inhibition of the activity of a member of the MAPEG family such as PGES (and particularly mPGES-1), LTC 4 synthase and/or FLAP is desired and/or required (e.g. inflammation), which method comprises administration of a therapeutically effective amount of a compound of the invention, as hereinbefore defined, to a patient suffering from, or susceptible to, such a condition.
  • a member of the MAPEG family such as a PGES (e.g. mPGES- 1), LTC 4 synthase and/or FLAP
  • a method of treatment of a disease in which inhibition of the activity of a member of the MAPEG family such as PGES (and particularly mPGES-1), L
  • 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, 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 or elixirs for oral administration, suppositories for rectal administration, sterile solutions or suspensions for parenteral or intramuscular administration, and the like.
  • 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, as hereinbefore defined, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • Preferred pharmaceutical formulations include those in which the active ingredient is present in at least 1% (such as at least 10%, preferably in at least 30% and most preferably in at least 50%) by weight. That is, the ratio of active ingredient to the other components (i.e. the addition of adjuvant, diluent and carrier) of the pharmaceutical composition is at least 1:99 (e.g. at least 10:90, preferably at least 30:70 and most preferably at least 50:50) by weight.
  • 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, as hereinbefore defined, or a pharmaceutically acceptable salt thereof 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 (e.g. NSAIDs and coxibs).
  • a combination product comprising:
  • composition (A) a compound of the invention, as hereinbefore defined; and (B) another therapeutic agent that is useful in the treatment of inflammation, wherein each of components (A) and (B) is formulated in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier.
  • Such combination products provide for the administration of a 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 a 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 a compound of the invention and the other therapeutic agent).
  • a pharmaceutical formulation including a compound of the invention, as hereinbefore defined, 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 as hereinbefore defined with another therapeutic agent that is useful in the treatment of inflammation, and a pharmaceutically-acceptable adjuvant, diluent or carrier.
  • kits of parts By “bringing into association”, we mean that the two components are rendered suitable for administration in conjunction with each other.
  • the two components of the kit of parts may be:
  • Compounds of the invention may be administered at varying doses.
  • Oral, pulmonary and topical dosages may range from between about 0.01 mg/kg 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.
  • 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.
  • the most preferred doses will range from about 0.001 to about 10 mg/kg/hour 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 are effective, and preferably selective, inhibitors of a member of MAPEG family, e.g. inhibitors of prostaglandin E synthases (PGES) and particularly microsomal prostaglandin E synthase- 1 (mPGES-1).
  • PGES prostaglandin E synthases
  • mPGES- 1 microsomal prostaglandin E synthase- 1
  • the compounds of the invention may reduce the formation of the specific arachidonic acid metabolite PGE 2 without reducing the formation of other COX generated arachidonic acid metabolites, and thus may not give rise to the associated side-effects mentioned hereinbefore.
  • Compounds of the invention may also 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 above-stated indications or otherwise.
  • pharmacokinetic profile e.g. higher oral bioavailability and/or lower clearance
  • Biological Test hi the assay mPGES-1 catalyses the reaction where the substrate PGH 2 is converted to PGE 2 .
  • mPGES-1 is expressed in E. coli and the membrane fraction is dissolved in 2OmM NaPi-buffer pH 8.0 and stored at -80°C.
  • mPGES- 1 is dissolved in O,1M KPi-buffer pH 7,35 with 2,5mM glutathione.
  • the stop solution consists of H 2 O / MeCN (7/3), containing FeCl 2 (25 mM) and HCl (0.15 M). The assay is performed at room temperature in 96-well plates.
  • Solvent B acetonitrile + 0.1% formic acid
  • Solvent B acetonitrile + 0.1% formic acid
  • the sub-title compound was prepared in accordance with Example 1 (c), using 4-
  • the sub-title compound was prepared in accordance with Example l(c), using 4- [5-bromo-2-(2-chloro-6-fluorophenyl)-lH-imidazol-4-yl]benzoic acid (150 mg, 0.38 mmol), which was reacted with benzene- 1 ,2-diamine to give 100 mg (54.3%) of crude N-(2-aminophenyl)-4-[5-bromo-2-(2-chloro-6-fluorophenyl)- 1 H- imidazol-4-yl]benzamide.
  • the sub-title compound was prepared in accordance with Example 1 (c), using 4- [2-(2-chloro-6-fluorophenyl)-lH-imidazol-4-yl]benzoic acid (140.0 mg, 0.442 mmol; see Example IQo)), which was reacted with 4-chloro-l,2-benzenediamine (63.0 mg, 0.442 mmol) to give 190.0 mg (97.4 %) crude N-(2-amino-5- chlorophenyl)-4-[2-(2-chloro-6-fluorophenyl)-lH-imidazol-4-yl]benzamide.
  • the sub-title compound was prepared in accordance with Example l(c). 4-[5- bromo-2-(2-chloro-6-fluorophenyl)-lH-imidazol-4-yl]benzoic acid (175 mg, 0.44 mmol; see Example 3(b)) was reacted with 1 ,2-diamino-4-fluorobenzene (55.8 mg, 0.44 mmol) to give 180 mg (80.8%) of the crude sub-title compound, N-(2- amino-5-fluorophenyl)-4-[5-bromo-2-(2-chloro-6-fluorophenyl)-lH-imidazol-4- yl]benzamide.
  • the sub-title compound was prepared in accordance with Example (Ic). 4-[2-(2- Chlorophenyl)-lH-imidazol-4-yl]benzoic acid (170 mg, 0.57 mmol) was reacted with 4-chloro-l,2-diaminobenzene (143 mg, 0.57 mmol) to give 240 mg (99.5%) of crude ⁇ /-(2-amino-5-chlorophenyl)-4-[2-(2-chlorophenyl)-lH-imidazol-4- yl]benzamide.
  • Example l(d) the title compound was prepared from N-(2- amino-5-chlorophenyl)-4-[2-(2-chlorophenyl)- 1 -methyl- 1 H-imidazol-4-yl] - benzamide by heating in concentrated acetic acid.
  • HPLC (column 4; method 2) retention time: 3.3 min.
  • Example l(d) the title compound was prepared from 4-[2-(2- chloro-6-fluorophenyl)- 1 H-imidazol-4-yl]-iV-(5-chloro-2-methylaminophenyl)- benzamide (see step (a) above) by heating the compound in concentrated acetic acid.
  • the sub-title compound was prepared from 4-[5- bromo-2-(2-chloro-6-fluorophenyl)-lH-imidazol-4-yl]benzoic acid (201mg, 0.58 mmol) and7V-butylbenzene-l,2-diamine (83mg, 0.58 mmol).
  • Example l(d) the title compound was prepared from 4-[2-(2- chloro-6-fluorophenyl)- 1 H-imidazol-4-yl]- ⁇ /-(4-chloro-2-methylaminophenyl)- benzamide by heating in concentrated acetic acid.
  • Example l(d) the title compound was prepared from 4-[2-(2- chloro-6-fluorophenyl)- 1 H-imidazol-4-yl] -N-(3 -chloro-2-methylaminophenyl)- benzamide (see step (a) above) by heating in concentrated acetic acid.
  • step (b) 4-[5-CHoro-2-f2-cMorophenylHH-imidazol-4-yl]benzoic acid 4-[5-Chloro-2-(2-chlorophenyl)-lH-imidazol-4-yl]benzoic acid methyl ester (see step (a) above; 800mg, 2.34 mmol) was hydrolysed in a mixture of sodium hydroxide (7 mL; 2N) and methanol (20 mL) at rt to yield the title compound (650mg, 84.7%).
  • Example l(d) the title compound was prepared from 7V-(2- amino-5-chlorophenyl)-4-[5-chloro-2-(2-chlorophenyl)-lH-imidazol-4-yl]- benzamide (see step (c) above) by heating in concentrated acetic acid. Yield: 81mg (34%)
  • Example l(c) the sub-title compound was prepared from 4-[5- bromo-2-(2-chloro-6-fluorophenyl)-lH-imidazol-4-yl]benzoic acid (217.6mg, 0.55 mmol) and 5-methyl-liV-methyl-l,2-aminobenzene (75mg, 0.55 mmol). Yield: 280mg (99.1%) C 24 Hi 9 BrClFN 4 O (513.79)
  • Example l(d) the title compound was prepared from 4-[5- bromo-2-(2-chloro-6-fluorophenyl)-lH-imidazol-4-yl]-N-(4-methyl-2-methyl- aminophenyl)benzamide (see step (a) above) by heating in concentrated acetic acid. Yield: 141mg (52%)
  • Example l(d) the title compound was prepared from 7V-(2- amino-5-trifluoromethylphenyl)-4-[5-bromo-2-(2-chloro-6-fluorophenyl)-lH- imidazol-4-yl]benzamide (see step (a) above) by heating in concentrated acetic acid.
  • Example l(c) the sub-title compound was prepared from 4-[5- bromo-2-(2-chloro-6-fluoro-phenyl)-lH-imidazol-4-yl]-benzoic acid (217.6mg, 0.55 mmol) and 1 ,2-diamino-4-methylbenzene (67.2mg, 0.55 mmol). Yield: 250mg (91.0%)
  • Example l(d) the title compound was prepared from N-(2- amino-5-methylphenyl)-4-[5-bromo-2-(2-chloro-6-fluorophenyl)-lH-imidazol-4- yljbenzamide (see step (a) above) by heating in concentrated acetic acid. Yield: 61mg (25.3%) C 23 Hi 5 BrClFN 4 (481.75)
  • Example l(c) the sub-title compound was prepared from 4-[5- bromo-2-(2-chloro-6-fluoro-phenyl)-lH-imidazol-4-yl]-benzoic acid (217.6mg,
  • Example l(d) the title compound was prepared from 4-[5- bromo-2-(2-chloro-6-fluoro-phenyl)-lH-imidazol-4-yl]-N-[2-(2-methoxy- ethylamino)-4-methyl-phenyl]-benzamide (see step ⁇ J(a) above) by heating in concentrated acetic acid.
  • Example l(d) the title compound was prepared from 2-chloro- 4-[2-(2-cUoro-6-fluoro-phenyl)-lH-imidazol-4-yl]-N-(2-methylamino-phenyl)- benzamide (see step (a) above) by heating in concentrated acetic acid.
  • Example l(c) the sub-title compound was prepared from 4-[5- bromo-2-(2-chloro-6-fluoro-phenyl)-lH-imidazol-4-yl]-benzoic acid (217.6mg, 0.55 mmol) and 5-methyl-liV-butyl-l,2-diaminobenzene (98.1mg, 0.55 mmol). Yield: 305mg (99.8%) C 27 H 25 BrClFN 4 O (555.87)
  • Example l(c) the sub-title compound was prepared from 4-[2- (2-chloro-phenyl)-lH-imidazol-4-yl]-benzoic acid (500.0mg, 1.67 mmol) and 2- amino-4-chloro-benzenethiol (445. Omg, 1.76 mmol).
  • Example l(d) the title compound was prepared from N-(2- amino-5-iodo-phenyl)-4-[5-bromo-2-(2-chloro-6-fluoro-phenyl)-lH-imidazol-4- yl]-benzamide (see step (a) above) by heating in concentrated acetic acid.
  • Example l(c) the sub-title compound was prepared from 4-[5- bromo-2-(2-chloro-6-fluoro-phenyl)-lH-imidazol-4-yl]-benzoic acid (217.6mg,
  • Example l(d) the title compound was prepared from 4-[5- bromo-2-(2-chloro-6-fluoro-phenyl)-lH-imidazol-4-yl]-N-(2-cyclohexylamino-4- methyl-phenyl)-benzamide (see step (a) above) by heating in concentrated acetic acid. Yield: lOlmg (34.7%)
  • Example l(c) the sub-title compound was prepared from 4-[5- bromo-2-(2-chloro-6-fluoro-phenyl)- 1 H-imidazol-4-yl]-benzoic acid (217.6mg,
  • Example l(d) the title compound was prepared from 4-[5- bromo-2-(2-chloro-6-fluoro-phenyl)-lH-imidazol-4-yl]-N-[2-(l-ethyl- propylamino)-4-methyl -phenyl] -benzamide (see step (a) above) by heating in concentrated acetic acid. Yield: 128mg (47.2%)
  • Example l(c) the sub-title compound was prepared from 4-[5- bromo-2-(2-chloro-6-fluoro-phenyl)- 1 H-imidazol-4-yl]-benzoic acid (217.6mg,
  • Example l(d) the title compound was prepared from N-(2- benzylammo-4-methyl-phenyl)-4-[5-bromo-2-(2-chloro-6-fluoro-phenyl)-lH- imidazol-4-yl]-benzamide (see step (a) above) by heating in concentrated acetic acid. Yield: 70mg (24.9%)
  • Example l(c) the sub-title compound was prepared from 4-[5- bromo-2-(2-chloro-6-fluoro-phenyl)-lH-imidazol-4-yl] -benzoic acid (217.6mg,
  • Example l(d) the title compound was prepared from 4-[5- bromo-2-(2-chloro-6-fluoro-phenyl)-lH-imidazol-4-yl]-N-[4-methyl-2-

Abstract

L'invention porte sur des composés de formule (I), dans laquelle les traits pointillés, X et R1 à R15 ont les significations données dans la description, et sur les sels pharmaceutiquement acceptables de ces composés. Ces composés et leurs sels sont utiles dans le traitement de maladies dans lesquelles une inhibition de l'activité d'un membre de la famille MAPEG est souhaitée et/ou requise, et en particulier dans le traitement de l'inflammation.
PCT/GB2008/000054 2007-01-12 2008-01-10 Dérivés de benzazole pour le traitement d'inflammations WO2008084218A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US88004707P 2007-01-12 2007-01-12
US60/880,047 2007-01-12
US92416707P 2007-05-02 2007-05-02
US60/924,167 2007-05-02

Publications (1)

Publication Number Publication Date
WO2008084218A1 true WO2008084218A1 (fr) 2008-07-17

Family

ID=39092831

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2008/000054 WO2008084218A1 (fr) 2007-01-12 2008-01-10 Dérivés de benzazole pour le traitement d'inflammations

Country Status (1)

Country Link
WO (1) WO2008084218A1 (fr)

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011023812A1 (fr) 2009-08-27 2011-03-03 Novasaid Ab Inhibiteurs de prostaglandine e synthase-1 (mpges1) microsomale
WO2011077313A1 (fr) 2009-12-22 2011-06-30 Pfizer Inc. Pipéridinecarboxamides en tant qu'inhibiteurs de mpges - 1
WO2011099832A2 (fr) * 2010-02-12 2011-08-18 Crystalgenomics, Inc. Nouveau composé de benzimidazole, son procédé de préparation et composition pharmaceutique le contenant
WO2010127152A3 (fr) * 2009-04-29 2011-09-29 Irm Llc Composés et compositions comme inhibiteurs de la prostaglandine e synthase-1 microsomale
WO2011131975A1 (fr) * 2010-04-23 2011-10-27 Convergence Pharmaceuticals Limited Inhibiteurs microsomaux de la prostaglandine e synthase-1
EP2495244A1 (fr) 2011-03-02 2012-09-05 NovaSaid AB Dérivés de piperidinyl-benzoimidazole en tant qu'inhibiteurs de mPGEs-1
JP2013512910A (ja) * 2009-12-04 2013-04-18 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング ロイコトリエン産生のベンゾイミダゾール阻害薬
US8957066B2 (en) 2011-02-28 2015-02-17 Biomarin Pharmaceutical Inc. Histone deacetylase inhibitors
US20150141657A1 (en) * 2011-02-15 2015-05-21 Council Of Scientific & Industrial Research 2-phenyl benzothiazole linked imidazole compounds as potential anticancer agents and process for the preparation thereof
WO2016024587A1 (fr) * 2014-08-13 2016-02-18 日本曹達株式会社 Composé de diarylimidazole et agent de lutte antiparasitaire
US9265734B2 (en) 2008-09-03 2016-02-23 Biomarin Pharmaceutical Inc. Compositions including 6-aminohexanoic acid derivatives as HDAC inhibitors
US9540395B2 (en) 2011-02-28 2017-01-10 Biomarin Pharmaceutical Inc. Histone deacetylase inhibitors
WO2017157735A1 (fr) 2016-03-15 2017-09-21 Bayer Cropscience Aktiengesellschaft Sulfonylamides substitués pour lutter contre les ravageurs
US10029988B2 (en) 2013-03-15 2018-07-24 Biomarin Pharmaceutical Inc. HDAC inhibitors
US10059723B2 (en) 2011-02-28 2018-08-28 Biomarin Pharmaceutical Inc. Histone deacetylase inhibitors

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006063466A1 (fr) * 2004-12-17 2006-06-22 Merck Frosst Canada Ltd. 1h-phénanthro[9,10-d]imidazoles substitués en 2 par un phényle ou un hétérocycle en tant qu'inhibiteurs de mpges-1
WO2006077366A1 (fr) * 2005-01-19 2006-07-27 Biolipox Ab Indoles utiles dans le traitement de l'inflammation

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006063466A1 (fr) * 2004-12-17 2006-06-22 Merck Frosst Canada Ltd. 1h-phénanthro[9,10-d]imidazoles substitués en 2 par un phényle ou un hétérocycle en tant qu'inhibiteurs de mpges-1
WO2006077366A1 (fr) * 2005-01-19 2006-07-27 Biolipox Ab Indoles utiles dans le traitement de l'inflammation

Cited By (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9265734B2 (en) 2008-09-03 2016-02-23 Biomarin Pharmaceutical Inc. Compositions including 6-aminohexanoic acid derivatives as HDAC inhibitors
US9796664B2 (en) 2008-09-03 2017-10-24 Biomarin Pharmaceutical Inc. Compositions including 6-aminohexanoic acid derivatives as HDAC inhibitors
WO2010127152A3 (fr) * 2009-04-29 2011-09-29 Irm Llc Composés et compositions comme inhibiteurs de la prostaglandine e synthase-1 microsomale
WO2011023812A1 (fr) 2009-08-27 2011-03-03 Novasaid Ab Inhibiteurs de prostaglandine e synthase-1 (mpges1) microsomale
JP2013512910A (ja) * 2009-12-04 2013-04-18 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング ロイコトリエン産生のベンゾイミダゾール阻害薬
WO2011077313A1 (fr) 2009-12-22 2011-06-30 Pfizer Inc. Pipéridinecarboxamides en tant qu'inhibiteurs de mpges - 1
WO2011099832A2 (fr) * 2010-02-12 2011-08-18 Crystalgenomics, Inc. Nouveau composé de benzimidazole, son procédé de préparation et composition pharmaceutique le contenant
WO2011099832A3 (fr) * 2010-02-12 2012-01-12 Crystalgenomics, Inc. Nouveau composé de benzimidazole, son procédé de préparation et composition pharmaceutique le contenant
WO2011131975A1 (fr) * 2010-04-23 2011-10-27 Convergence Pharmaceuticals Limited Inhibiteurs microsomaux de la prostaglandine e synthase-1
US20150141657A1 (en) * 2011-02-15 2015-05-21 Council Of Scientific & Industrial Research 2-phenyl benzothiazole linked imidazole compounds as potential anticancer agents and process for the preparation thereof
US9187467B2 (en) * 2011-02-15 2015-11-17 Council Of Scientific And Industrial Research 2-phenyl benzothiazole linked imidazole compounds as potential anticancer agents and process for the preparation thereof
US9908899B2 (en) 2011-02-28 2018-03-06 Biomarin Pharmaceutical Inc. Histone deacetylase inhibitors
US10526346B2 (en) 2011-02-28 2020-01-07 Biomarin Pharmaceutical Inc. Histone deacetylase inhibitors
US8957066B2 (en) 2011-02-28 2015-02-17 Biomarin Pharmaceutical Inc. Histone deacetylase inhibitors
US9512143B2 (en) 2011-02-28 2016-12-06 Biomarin Pharmaceutical Inc. Histone deacetylase inhibitors
US9540395B2 (en) 2011-02-28 2017-01-10 Biomarin Pharmaceutical Inc. Histone deacetylase inhibitors
US10301323B2 (en) 2011-02-28 2019-05-28 Biomarin Pharmaceutical Inc. Histone deacetylase inhibitors
US10280182B2 (en) 2011-02-28 2019-05-07 Biomarin Pharmaceutical Inc. Histone deacetylase inhibitors
US10059723B2 (en) 2011-02-28 2018-08-28 Biomarin Pharmaceutical Inc. Histone deacetylase inhibitors
US10981933B2 (en) 2011-02-28 2021-04-20 Biomarin Pharmaceutical Inc. Histone deacetylase inhibitors
WO2012117062A1 (fr) 2011-03-02 2012-09-07 Novasaid Ab Dérivés de pipéridinyl benzoimidazole comme inhibiteurs de mpges-1
EP2495244A1 (fr) 2011-03-02 2012-09-05 NovaSaid AB Dérivés de piperidinyl-benzoimidazole en tant qu'inhibiteurs de mPGEs-1
US10029988B2 (en) 2013-03-15 2018-07-24 Biomarin Pharmaceutical Inc. HDAC inhibitors
US10428028B2 (en) 2013-03-15 2019-10-01 Biomarin Pharmaceutical Inc. HDAC inhibitors
US10021880B2 (en) 2014-08-13 2018-07-17 Nippon Soda Co., Ltd. Diarylimidazole compound and harmful organism control agent
JPWO2016024587A1 (ja) * 2014-08-13 2017-05-25 日本曹達株式会社 ジアリールイミダゾール化合物および有害生物防除剤
CN106573894A (zh) * 2014-08-13 2017-04-19 日本曹达株式会社 二芳基咪唑化合物和有害生物防除剂
WO2016024587A1 (fr) * 2014-08-13 2016-02-18 日本曹達株式会社 Composé de diarylimidazole et agent de lutte antiparasitaire
JP2020114827A (ja) * 2014-08-13 2020-07-30 日本曹達株式会社 ジアリールイミダゾール化合物および有害生物防除剤
WO2017157735A1 (fr) 2016-03-15 2017-09-21 Bayer Cropscience Aktiengesellschaft Sulfonylamides substitués pour lutter contre les ravageurs

Similar Documents

Publication Publication Date Title
WO2008084218A1 (fr) Dérivés de benzazole pour le traitement d'inflammations
US9040565B2 (en) 1H-benzimidazole-5-carboxamides as anti-inflammatory agents
EP1778633B1 (fr) Indoles utilisables pour le traitement d'inflammations
EP1841735B1 (fr) Indoles utiles dans le traitement de l'inflammation
US20090042949A1 (en) Indoles Useful in the Treatment of Inflammation
US20090048285A1 (en) Pyrrolopyridines Useful in the Treatment of Inflammation
WO2008071944A1 (fr) Benzoxasoles utiles dans le traitement de l'inflammation
ZA200610357B (en) Indoles useful in the treatment of inflammation
WO2008129276A1 (fr) Disulfonamides utiles dans le traitement de l'inflammation
WO2008009924A2 (fr) Indoles utiles dans le traitement de l'inflammation
EP1765775B1 (fr) Indoles utiles dans le traitement de l'inflammation
WO2010076566A2 (fr) Indoles utilisables dans le traitement de l'inflammation

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 08700151

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 08700151

Country of ref document: EP

Kind code of ref document: A1