WO2008009924A2 - Indoles utiles dans le traitement de l'inflammation - Google Patents

Indoles utiles dans le traitement de l'inflammation Download PDF

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WO2008009924A2
WO2008009924A2 PCT/GB2007/002704 GB2007002704W WO2008009924A2 WO 2008009924 A2 WO2008009924 A2 WO 2008009924A2 GB 2007002704 W GB2007002704 W GB 2007002704W WO 2008009924 A2 WO2008009924 A2 WO 2008009924A2
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formula
compound
compounds
group
single bond
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PCT/GB2007/002704
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WO2008009924A3 (fr
Inventor
Benjamin Pelcman
Kristofer Olofsson
Martins Katkevics
Vita Ozola
Edgars Suna
Ivars Kalvins
Pavels Arsenjans
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Biolipox Ab
Boehringer Ingelheim International Gmbh
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Publication of WO2008009924A2 publication Critical patent/WO2008009924A2/fr
Publication of WO2008009924A3 publication Critical patent/WO2008009924A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • This invention relates to novel phamaceutically-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 MGST3).
  • 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 cardioavascular 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 5 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 disease0
  • COX cyclooxygenase
  • COXs metabolise arachidonic acid to the unstable intermediate prostaglandin H 2 0 (PGH 2 ).
  • PGH 2 is further metabolized to other prostaglandins including PGE 2 , PGF 2 ⁇ , PGD 2 , prostacyclin and thromboxane A 2 .
  • PGE 2 arachidonic acid metabolites are known to have pronounced physiological and pathophysiological activity including pro-inflammatory effects.
  • 5 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).
  • NSAIDs non-steroidal antiinflammatory drugs
  • coxibs selective COX-2 inhibitors
  • 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 CysLTj. It may be hypothesised that better control of asthma, and possibly also COPD, maybe 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.
  • Indole-based compounds have been disclosed in international patent applications WO 96/03377, WO 01/00197, WO 03/044014 and WO 03/057670, US patents Nos. 5,189,054, 5,294,722, 4,960,786, 5,236,916 and 5,374,615 and European patent applications EP 429 257, EP 483 881, EP 547 556, EP 639 573, EP 1 314 733 and EP 488 532.
  • none of these documents disclose or suggest the use of such compounds in the treatment of inflammation.
  • Indoles have also been disclosed for potential use in the treatment of inflammation in international patent applications WO 99/43672, WO 98/08818, WO 99/43654, WO 99/43651, WO 99/05104 and WO 03/029212, European patent application EP 986 666 and US patents Nos. 6,500,853 and 6,630,496.
  • indole-2-carboxylates in which an aromatic group is directly attached via the indole nitrogen.
  • 2005/005415 discloses such compounds for use as inhibitors of mPGES and thus in the treatment of inflammation.
  • indole-2-carboxylates in which an aromatic group is directly attached via the indole nitrogen.
  • International patent applications WO 2005/123675, WO 2005/123673 and WO 2005/123674 disclose indoles for use as inhibitors of mPGES and thus in the treatment of inflammation.
  • indoles which are substituted at the benzenoid moiety of the indole ring with an aromatic group that is attached via a linking group.
  • unpublished patent application PCT/GB2005/004978 discloses inter alia indole-2-carboxylic acids that are substituted at the benzenoid moiety of the indole with an aromatic group that is attached via a linker group.
  • Unpublished patent application PCT/GB2005/0049828 also discloses similar indoles but in which the indole-2-substituent is inter alia a carboxylic acid isostere.
  • R 1 and E independently represent an aryl group or a heteroaryl group, both of which groups are optionally substituted by one or more substituents selected from
  • R 7 represents C 1-6 alkyl, optionally substituted by one or more substituents selected from W 1 , or R 7a ; or
  • R 7 and R 8 are linked together with the carbon atom to which they are attached to form a 3- to 6-membered ring, which ring contains at least one (e.g. one) unsaturation (e.g. a triple or, preferably, a double bond), optionally contains a heteroatom and is optionally substituted by one or more substituents selected from halo and C 1-3 alkyl, which latter group is optionally substituted by one or more halo substituents;
  • R 7a and R 8 independently represent -OR a , -N(R b )(R°) or -SR d ; .
  • R ⁇ and R 8b independently represent hydrogen, -OR e , -N(R f )(R g ), -SR h or C 1-6 allcyl optionally substituted by one or more substituents selected from W ; or R 713 and R 8b are linked together to form, together with the carbon atom to which they are necessarily attached, a 3- to 6-membered ring optionally containing 1 to 3 heteroatoms and 1 to 3 unsaturations (e.g. double bonds) and which ring is optionally substituted by one or more substituents selected from C 1-6 alkyl (which is optionally substituted by one or more halo atoms) and W ;
  • R a , R b , R G , R d , R e , R f , R ⁇ and R h independently represent H or C 1-6 alkyl optionally substituted by one or more substituents selected from " w ; or any pair of R b and R°, or R f and R ⁇ are linked together with the nitrogen atom to which they are necessarily attached to form a 3- to 6-membered ring optionally containing 1 to 3 heteroatoms and 1 to 3 unsaturations (e.g. double bonds) and which ring is optionally substituted by one or more substituents selected from C 1-6 alkyl (which is optionally substituted by one or more halo atoms) and W ;
  • X 1 represents H, halo, -N(R 9a )-J-R 10a or -Q-X 2 ;
  • J represents a single bond, -C(O)- or -S(O) m -;
  • Q represents a single bond, -O-, -C(O)- or -S(O) m -;
  • X 2 represents: (a) an aryl group or a heteroaryl group, both of which are optionally substituted by one or more substituents selected from A; or (b) C 1-8 alkyl or a heterocycloalkyl group, both of which are optionally substituted by one or more substituents selected from G 1 and/or Z ;
  • T represents: (a) a single bond
  • (iii) may comprise an additional 3- to 8-membered ring formed between any one or more (e.g. one or two) members of the C 1-8 alkylene or C 2-S heteroalkylene chain, which ring optionally contains 1 to 3 heteroatoms and/or 1 to 3 unsaturations (for example double or triple bonds) and which ring is itself optionally substituted by one or more substituents selected from G 1 and/or Z 1 ;
  • T 1 and T 2 represents a C 1-8 alkylene or a C 2-8 heteroalkylene chain, both of which latter two groups:
  • (iii) may comprise an additional 3- to 8-membered ring formed between any one or more (e.g. one or two) members of the C 1-8 alkylene or C 2-S heteroalkylene chain, which ring optionally contains 1 to 3 heteroatoms and/or 1 to 3 unsaturations (for example double or triple bonds) and which ring is itself optionally substituted by one or more substituents selected from G 1 and/or Z 1 ; and the other represents an arylene group or a heteroarylene group chain, both of which groups are optionally substituted by one or more substituents selected from
  • W x represents -O- or -S(O) m -;
  • n represents, on each occasion when mentioned above, 0, 1 or 2;
  • Y represents -C(H)(CF 3 )OH 5 -C(O)CF 3 , -C(OH) 2 CF 3 , -C(O)OR 9b , -S(O) 3 R 9c , -P(O)(OR 9d ) 2 , -P(O)(OR 9e )N(R 10f )R 9f , -P(O)(N(R 10g )R 9g ) 2 , -B(OR 9h ) 2 , -C(CF 3 ) 2 OH, -S(O) 2 N(R 10i )R 9i or any one of the following groups:
  • R 6 , R 9a to R 9x , R 1Oa , R 1Of , R 1O ⁇ , R 1Oi and R 1Oj independently represent, on each occasion when mentioned above:
  • A represents, on each occasion when mentioned above:
  • G 1 represents, on each occasion when mentioned above, halo, cyano, -N 3 , -NO 2 , -ONO 2 or -A ⁇ R 113 ; wherein A 1 represents a single bond or a spacer group selected from -C(O)A 2 -,
  • a 2 represents a single bond, -0-, -N(R 12b )- or -C(O)-;
  • a 3 represents a single bond, -O- or -N(R 12c )-;
  • a 4 and A 5 independently represent a single bond, -C(O)-, -C(0)N(R 12d )-, -C(O)O-,
  • G 2 represents, on each occasion when mentioned above, halo, cyano, -N 3 , -NO 2 , -ONO 2 or -A 6 -R 13a ;
  • a 6 represents a single bond or a spacer group selected from -C(O)A 7 -, -S(O) 2 A 8 -, -N(R 14a )A 9 - or -OA 10 -, in which: A 7 represents a single bond, -0-, -N(R 14b )- or -C(O)-;
  • a 8 represents a single bond, -O- or -N(R 14c )-;
  • a 9 and A 10 independently represent a single bond, -C(O)-, -C(O)N(R 14d )-, -C(O)O-, -S(O) 2 - or -S(O) 2 N(R 146 )-;
  • R 14d , R 14e and R 14f are independently selected from: i) hydrogen; ii) an aryl group or a heteroaryl group, both of which are optionally substituted by one or more substituents selected from G 3 ; iii) C 1-8 alkyl or a heterocycloalkyl group, both of which are optionally substituted by G 3 and/or Z 3 ; or ⁇ any pair of R lla to R llc and R 12a to R 12f , and/or R 13a to R 13c and R 14a to R 14f , may, for example when present on the same or on adjacent atoms, be linked together to form with those, or other relevant, atoms a further 3- to 8-membered ring, optionally containing 1 to 3 hetero atoms and/or 1 to 3 double bonds, which ring is optionally substituted by one or more substituents selected from G 3 and/or Z 3 ; ⁇
  • G 3 represents, on each occasion when mentioned above, halo, cyano, -N 3 , -NO 2 ,
  • A represents a single bond or a spacer group selected from -C(O)A -, -S(O) 2 A 13 -, -N(R 16a )A 14 - or -OA 15 -, in which: A 12 represents a single bond, -0-, -N(R 16b )- or -C(O)-; A 13 represents a single bond, -O- or -N(R 160 )-; T/GB2007/002704
  • a 14 and A 15 independently represent a single bond, -C(O)-, -C(0)N(R 16d )-, -C(O)O-, -S(O) 2 - or -S(O) 2 N(R 166 )-;
  • R 17a , R 17b , R 17c , R 17d , R 17e , R 17f , R 18a , R 18b and R 18 ° are independently selected from hydrogen and C 1-4 alkyl, which latter group is optionally substituted by one or more halo groups;
  • 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 (entgegeri) and Z (zusammen) 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 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, and C 1-q alkylene, groups (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 two or three, as appropriate) of carbon atoms, be branched-chain, and/or, in the case of alkyl, cyclic (so forming a C 3-q cycloalkyl group). Further, when there is a sufficient number (i.e. a minimum of four) of carbon atoms, such groups may also be part cyclic. Such alkyl and alkylene groups may also be saturated or, when there is a sufficient number (i.e.
  • a rmnimum of two) of carbon atoms be unsaturated (forming, for example, in the case of alkyl, a C 2-q alkenyl or a C 2-q alkynyl group or, in the case of alkylene, a C 2-q alkenylene or a C 2-q alkynylene group).
  • Cycloalkyl groups that may be mentioned include non-aromatic C 3-16 , such as C 3-1O , cycloalkyl groups.
  • C 3-q cycloalkyl groups may be monocyclic or bicyclic alkyl groups, which cycloalkyl groups may further be bridged (so forming, for example, fused ring systems such as three fused cycloalkyl groups).
  • Such cycloalkyl groups may be saturated or unsaturated containing one or more double or triple bond (forming for example a C 3-q cycloalkenyl or a C 8-q cycloalkynyl group).
  • Cycloalkyl groups that may be mentioned include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclooctynyl, bicycloheptyl, bicyclooctyl, and bicyclooctenyl, as well as bridged cycloalkyl groups, such as adamantyl, noradamantyl, norbornane, norbornene and norbornadiene groups.
  • Substituents may be attached at any point on the cycloalkyl group. Further in the case where the substituent is another cyclic compound, then the cyclic substituent may be attached through a single atom on the cycloalkyl group, forming a so-called "spiro"-compound.
  • Preferred cycloalkyl groups include optionally substituted C 3- g cycloalkyl groups, which groups optionally contain one unsaturation (e.g. a double bond).
  • Cycloalkyl groups that may be mentioned include optionally substituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl (e.g. cyclopenten-1-yl), cyclohexenyl (e.g. cyclohexen-1-yl) and norbornanyl (e.g. norbornan-2-yl).
  • halo when used herein, includes fluoro, chloro, bromo and iodo.
  • 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 3-q heterocycloalkynyl group.
  • C 2-q heterocycloalkyl groups that may be mentioned include 7- azabicyclo[2.2. ljheptanyl, 6-azabicyclo[3.1. ljheptanyl, 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.
  • ljheptanyl 6- oxabicyclo[3.2.1]octanyl, oxetanyl, oxiranyl, piperazinyl, piperidinyl, pyranyl, pyrazolidinyl, pyrrolidinonyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, sulfolanyl, 3- sulfolenyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydropyridyl (such as 1,2,3,4-tetrahydropyridyl and 1,2,3,6-tetrahydro ⁇ yridyl), thietanyl, thiiranyl, thiolanyl, thiomorpholinyl, trithianyl (including 1,3,5-trithianyl), tropanyl and the like.
  • Substituents on heterocycloallcyl groups may, where appropriate, be located on any atom in the ring system including a heteroatom. Further, in the case where the other substituent is another cyclic compound, then the cyclic compound may be attached through a single atom on the heterocycloalkyl group, forming a so- called "s ⁇ iro"-com ⁇ ound.
  • 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 JV- or S- oxidised form.
  • heterocycloalkyl groups include optionally substituted 5 to 6-membered heterocyclic groups containing at least one oxygen or, more preferably, nitrogen atom and, optionally, a further nitrogen and/or oxygen atom.
  • Heterocycloalkyl groups that may be mentioned include optionally substituted pyrrolidinyl (e.g. pyrrolidin-1-yl), morpholinyl (e.g. 4-morpholin-l-yl), piperazinyl (e.g. piperazin-1-yl), piperidinyl (e.g. piperidin-1-yl and piperidin-4-yl) and tetrahydropyridyl (e.g. 1,2,3,6- tetrahydropyridin-2-yl) groups.
  • pyrrolidinyl e.g. pyrrolidin-1-yl
  • morpholinyl e.g. 4-morpholin-l-yl
  • piperazinyl e.g. piperazin
  • R 71 ' and R 8b are as hereinbefore defined and the asterisks (at each point) indicate the point of attachment with the group E or with the benezenoid moiety of the indole ring of formula I (as appropriate).
  • bicyclic when employed in the context of cycloalkyl and heterocycloalkyl groups refers to such groups in which the second ring is formed between two adjacent atoms of the first ring.
  • bridged when employed in the context of cycloalkyl or heterocycloalkyl groups refers to monocyclic or bicyclic groups in which two non-adjacent atoms are linked by either an alkylene or heteroalkylene chain (as appropriate).
  • Aryl groups that may be mentioned include C 6-14 (such as C 6-13 (e.g. C 6-1 o)) aryl groups.
  • Such groups may be monocyclic, bicyclic or tricyclic and have between 6 and 14 ring carbon atoms, in which at least one ring is aromatic.
  • C 6-14 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.
  • 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 14 (e.g. 10) members. 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).
  • Heterocyclic groups that may be mentioned include benzothiadiazolyl (including 2,1,3-benzothiadiazolyl), isothiochromanyl and, more preferably, acridinyl, benzimidazolyl, benzodioxanyl, benzodioxepinyl, benzodioxolyl (including 1,3- benzodioxolyl), benzofuranyl, benzofurazanyl, benzothiazolyl, benzoxadiazolyl (including 2,1,3-benzoxadiazolyl), benzoxazinyl (including 3 5 4-dihydro-2i?-l,4- benzoxazinyl), benzoxazolyl, benzomorpholinyl, benzoselenadiazolyl (including 2,1,3-benzoselenadiazolyl), benzothienyl, carbazolyl, chromanyl, cinnolinyl, furanyl, imidazolyl,
  • 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 may also be in the 7V- or S- oxidised form.
  • Heteroatoms that may be mentioned include phosphorus, silicon, boron, tellurium, selenium and, preferably, oxygen, nitrogen and sulphur.
  • R 2 to R 5 this will be understood by the skilled person to mean R 2 , R 3 , R 4 and R 5 inclusively.
  • any pair of R lla to R Uc and R 12a to R 12f may be linked as hereinbefore defined.
  • R lla to R llc groups, and R 12a to R 12f groups may be attached to a single nitrogen atom (e.g. R lla and R 12a or R llc and R 12f ), which may form part of the ring.
  • R 9a to R 9x this will be understood by the skilled person to mean R 9a , R 9b , R 9 °, R 9d , R 9e , R 9f , R 9g , R 9h , R 9i , R 9j , R 9k , R 9m , R 9n , R 9p , R 9q , R 9r , R 9s , R 9t , R 9u , R 9v , R 9w and R 9x inclusively.
  • R 9a to R 9x and R 1Oa , R 1Of , R 1Og , R 10i or R 10j may be linked together to form a ring as hereinbefore defined.
  • R 9a to R 9x , R 1Oa , R 10f , R 1Og , R 1Oi and R 1Oj groups may be attached to (a) a single nitrogen atom (e.g. R 9f and R 1Of ), or (b) a nitrogen atom and a J group (i.e. R 9a and R 1Oa ), which also form part of the ring, or two R 9a to R 9x (e.g. two R 9d ) groups may be attached to different oxygen atoms (for example in a 1,3-relationship) all of which may form part of the ring.
  • Still further compounds of the invention include those in which, when one of the groups R 2 , R 3 , R 4 and R 5 represents -D-E and one or more of the other groups represent G 1 then, when G 1 represents -A ⁇ R 1 la , A 1 represents a spacer group selected from -C(O)A 2 -, -S(O) 2 A 3 -, -N(R 12a )A 4 - or -OA 5 -.
  • Ci- 8 alkyl or a heterocycloalkyl group which groups are substituted by G 1 , and, in either case, G 1 is -A ⁇ R 11 * 1 , then A represents a single bond or a spacer group selected from -C(O)-, -S(O) 2 -, -S(O) 2 N(R 12c )-, -N(R 12a )A 4 - or -OA 5 -.
  • Preferred compounds of the invention include those in which: R 6 and, more particularly, R 9a to R 9x , R 1Oa , R 10f , R 1Og , R 1Oi and R 10j independently represent, on each occasion when mentioned above:
  • C 1-8 alkyl or a heterocycloalkyl group both of which are optionally substituted by one or more substituents selected from G 1 and/or Z 1 ; or any pair of R 9a to R 9x and R 1Oa , R 1Of , R 1Og , R 10i or R 1Oj , may be linked together to form, along with the atom(s) and/or group(s) to which they are attached, a 3- to 8- membered ring, optionally containing 1 to 3 heteroatoms and/or 1 to 3 double bonds, which ring is optionally substituted by one or more substituents selected from G 1 and/or Z 1 .
  • R 4 or, more preferably, R 3 represents -D-E;
  • Q represents -O 5 -S- or, more preferably, a single bond
  • A represents G 1 or C 1-6 alkyl optionally substituted by one or more G 1 groups
  • X 2 represents C 1-6 (e.g. C 1-4 ) alkyl or heterocycloalkyl, both of which are optionally substituted by one or more (e.g. one) G 1 and/or Z 1 groups;
  • R 7 represents C 1-6 alkyl optionally substituted as hereinbefore defined
  • R 8 represents -0R a ;
  • R 713 and R 8b independently represent H, -0R e or C 1-4 (e.g. C 1-3 ) alkyl optionally substituted by one or more (e.g. one) W 2 substituent(s); or R 713 and R 8b are linked together to form a 3- to 6-membered ring optionally containing 1 to 3 (e.g. 1 or 2) heteroatoms and which ring is optionally substituted by one or more substitutents selected from C 1-6 alkyl and W ;
  • R a , R b , R c and R d independently represent H or C 1-4 alkyl optionally substituted by one or more substituents selected from w ;
  • R e , R f , R g and R h independently represent H or, preferably, C 1-4 (e-g- C 1-3 ) alkyl optionally substituted by one or more halo (e.g. fluoro) atoms;
  • R 9a to R 9x independently represent H or C 1-6 alkyl (e.g. C 1-2 alkyl);
  • R 1Oa , R lof , R 10g 5 R loi and R 10j independently represent heteroaryl or, preferably, H or C 1-6 (such as C 1-4 (e.g. C 1-3 )) alkyl, which group is optionally substituted by one or more (e.g. one) groups selected from G 1 ; or any pair of R 9a to R 9x and R 1Oa , R 10f , R 1Og , R loi or R 10j are linked to form a 4- to
  • 7-membered (e.g. 5- or 6-membered) ring which ring may contain (in addition to the nitrogen atom to which R 9a to R 9x is attached) a further heteroatom (e.g. nitrogen or oxygen) and which ring is optionally substituted by one or more (e.g. two) Z 1 groups;
  • G 1 represents halo, cyano, -NO 2 or -A ⁇ R 1 la ;
  • a 1 represents a single bond, -C(O)A 2 -, -N(R 12a )A 4 - or -OA 5 -;
  • a 2 represents -O- or -N(R 12b )-;
  • a 4 and A 5 independently represent -C(O)-, -C(O)N(R 12d )-, -C(O)O- or a single bond;
  • R lla , R llb , R Uo , R 13a , R 13b and R 13c independently represent hydrogen, an aryl group, a heteroaryl group, a heterocyclo alkyl group (such as C 4-8 heterocycloalkyl, which group contains one oxygen or, more preferably, nitrogen atom and, optionally, a further nitrogen or oxygen atom) or, preferably, C 1-6 (e.g. C 1-4 ) alkyl, which latter four groups are optionally substituted by one or more G groups and/or (in the case of alkyl and heterocycloalkyl) Z 3 groups;
  • R 12a , R 12b , R 12c , R 12d , R 12e , R 12f , R 14a , R 14b , R 14c , R 14d , R 14e and R 14f independently represent H or C 1-2 alkyl;
  • G 2 represents cyano, -N 3 or, more preferably, halo, -NO 2 or -A 6 -R I3a ;
  • a 6 represents -N(R 14a )A 9 - or -OA 10 -;
  • a 9 represents ⁇ C(O)N(R 14d )- > -C(O)O- or, more preferably, a single bond or
  • a 10 represents a single bond
  • G 3 represents halo, -NO 2 or -A 1 ! -R 15a ;
  • a 11 represents -N(R 16a )- or -0-;
  • R 19a , R 19b and R 19c independently represent H or C 1-4 (e.g. C 1-3 ) alkyl optionally substituted by one or more halo (e.g. fluoro) atoms.
  • Preferred aryl and heteroaryl groups that R , E and (when they represent such aryl or heteroaryl groups) X 2 , R 9a to R 9x , R 1Oa , R 10f , R 1Og , R 1Oi and R 1Oj may represent include optionally substituted phenyl, naphthyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl (e.g 1-imidazolyl, 2-imidazolyl or 4-imidazolyl), oxazolyl, isoxazolyl, thiazolyl, pyridyl (e.g.
  • R 1 examples include optionally substituted pyridyl (e.g. 2-pyridyl or 3- pyridyl), imidazolyl and, especially, phenyl.
  • pyridyl e.g. 2-pyridyl or 3- pyridyl
  • imidazolyl e.g. imidazolyl
  • phenyl e.g. phenyl
  • Preferred values of E include optionally substituted 1,3-benzodioxolyl (e.g. 1,3- benzodioxol-5-yl), preferably, pyridyl (e.g. 2- or 3-pyridyl), imidazolyl, more preferably quinolinyl (e.g. 3-quinolinyl), and particularly phenyl.
  • 1,3-benzodioxolyl e.g. 1,3- benzodioxol-5-yl
  • pyridyl e.g. 2- or 3-pyridyl
  • imidazolyl more preferably quinolinyl (e.g. 3-quinolinyl)
  • quinolinyl e.g. 3-quinolinyl
  • C 1-4 alkyl including ethyl, n-propyl, isopropyl, «-butyl or, preferably, methyl or t-butyl), n-pentyl, isopentyl, n-hexyl or isohexyl), cyclic (e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), part-cyclic (e.g. cyclopropylmethyl), unsaturated (e.g.
  • halo e.g. fiuoro
  • heterocycloalkyl such as a C 4-5 heterocycloalkyl group, preferably containing a nitrogen atom and, optionally, a further nitrogen or oxygen atom, so forming for example morpholinyl (e.g. 4-morpholinyl), piperazinyl (e.g.
  • 4- ⁇ iperazinyl) or piperidinyl (e.g. 1-piperidinyl and 4- ⁇ iperidinyl) or pyrrolidinyl (e.g. 1- pyrrolidinyl), which heterocycloalkyl group is optionally substituted by one or more (e.g. one or two) substituents selected from C 1-3 alkyl (e.g. methyl) and 0; -OR 20.
  • piperidinyl e.g. 1-piperidinyl and 4- ⁇ iperidinyl
  • pyrrolidinyl e.g. 1- pyrrolidinyl
  • R 20 and R 21 independently represent, on each occasion when mentioned above, H or C 1-6 alkyl, such as ethyl, n-propyl, n-butyl, t-butyl or, preferably, isopropyl or methyl (which allcyl groups are optionally substituted by one or more halo (e.g. fluoro) groups (to form e.g. a trifluoromethyl group)).
  • halo e.g. fluoro
  • R 6 include C 1-4 alkyl and, particularly, H.
  • Particularly preferred compounds of the invention include those in which:
  • T represents a single bond
  • Y represents -C(O)OR 9b ;
  • R 9b represents C 1-4 alkyl and, particularly, H.
  • More preferred compounds of the invention include those in which: one of R 4 and, more preferably, R 3 represents -D-E and the other (more preferably) represents H;
  • X 1 represents -N(R 9a )-J-R 10a or, more preferably, C 1-3 alkyl (e.g. methyl), heterocycloalkyl (which latter two groups are optionally substituted by
  • G 1 and, preferably, -N(R 12a )R lla , -OR lla , -R lla or halo (e.g. fluoro or chloro)), H or halo (e.g. fluoro or chloro);
  • R 2 represents chloro or, preferably H
  • R 5 represents H;
  • A represents G 1 , or C 1-6 (e.g. C 1-4 ) alkyl (e.g. cyclohexyl or, preferably, methyl or t-butyl) optionally substituted by one or more G 1 groups;
  • G 1 represents cyano or, preferably, fluoro, chloro, -NO 2 or -A ⁇ R 118 ;
  • a 4 represents -C(O)- or, preferably, a single bond
  • a 5 represents a single bond
  • R 9a represents H or methyl
  • R 1Oa represents methyl, t-butyl, pyridyl (e.g. 3- ⁇ yridyl) or propyl (e.g. ⁇ -propyl optionally substituted by a G 1 (e.g. -N(R 12 ⁇ R 1 la ) group); or R 9a and R 1Oa are linked to form a 5- or 6-membered (e.g. 5-membered) ring, which is substituted by one Z group;
  • R lla , R llb and R l lc independently represent a phenyl group, a heteroaryl (such as tetrazolyl (e.g. 5-tetrazolyl), imidazolyl (e.g. 4-imidazolyl or 2-imidazolyl) or a pyridyl (e.g. 3-pyridyl, 4-pyridyl or, especially, 2-pyridyl)) group, or, more preferably, C 1-3 alkyl (e.g. methyl or isopropyl) all of which are optionally substituted by one or more G 3 groups;
  • a heteroaryl such as tetrazolyl (e.g. 5-tetrazolyl), imidazolyl (e.g. 4-imidazolyl or 2-imidazolyl) or a pyridyl (e.g. 3-pyridyl, 4-pyridyl or, especially, 2-pyridyl))
  • R 12a , R 12b , R 12c , R 12d , R 12e and R 12f independently represent H or methyl
  • G represents halo (e.g. fluoro); W 1 , W 2 and W 4 independently represent fluoro, -OCH 3 , -OCH 2 CH 3 , -OCHF 2 ,
  • R 19a , R 19b and R 19c independently represent H or C 1-2 alkyl (e.g. methyl), which latter group is optionally substituted by one or more halo (e.g. fluoro) atoms (so forming, for example, a difluoro- or trifluoro-rnethyl group).
  • halo e.g. fluoro
  • X 1 represents halo
  • R 1 and E independently represent a 6-membered aryl (e.g. phenyl) ring optionally substituted, for example at thep ⁇ r ⁇ -position relative to the point of attachment of the R 1 group to the indole ring, or the E group to the D group, respectively, with a (e.g. a single) G 1 group;
  • aryl e.g. phenyl
  • R 2 , R 4 and R 5 independently represent H
  • R 3 represents -D-E
  • D represents -C(R 7 )(R 8 )-;
  • G 1 represents -A ⁇ R 113 ;
  • a 1 represents a single bond or, more preferably, -OA 5 -;
  • R 7 represents Cj -3 alkyl (e.g. methyl or ethyl) optionally substituted by one or more halo (e.g. fluoro) atoms (so forming, for example, a difluoromethyl or trifluoromethyl group);
  • Particularly preferred compounds of the invention include those in which:
  • R represents 4-isopropoxyphenyl
  • R 7 represents -CH 3 , -CH 2 CH 3 , -CHF 2 or -CF 3 ;
  • R 8 represents -OH, -OCH 3 , -OCH 2 CH 3 , -OCHF 2 or -OCF 3 ;
  • R 713 and R 8b independently represent H, -CH 3 , -CH 2 CH 3 , -CHF 2 , -CF 3 , -OCH 3 ,
  • D represents -C(OH)(CF 3 )-
  • E represents 4-trifluoromethoxyphenyl
  • X 1 represents chloro
  • Particularly preferred compounds of the invention include those of the examples described hereinafter.
  • L 1 represents a suitable leaving group such as chloro, bromo, iodo, a sulfonate group (e.g. -OS(O) 2 CF 3 , -OS(O) 2 CH 3 , -OS(O) 2 PhMe or a nonaflate) or -B(OH) 2 and R 1 is as hereinbefore defined, for example optionally in the presence of an appropriate metal catalyst (or a salt or complex thereof) such as Cu, Cu(OAc) 2 , CuI (or Cul/diamine complex), Pd(OAc) 2 , Pd 2 (dba) 3 or NiCl 2 and an optional additive such as Ph 3 P, 2,2'-bis(diphenylphosphino)-l,r-binaphthyl, xantphos, NaI or an appropriate crown ether such as 18-crown-6-benzene, in the presence of an appropriate base such as NaH, Et 3 N, pyridine, i ⁇ yl
  • This reaction may be carried out at room temperature or above (e.g. at a high temperature, such as the reflux temperature of the solvent system that is employed) or using microwave irradiation;
  • L 2 represents a suitable leaving group such as chloro, bromo, iodo, -B(OH) 2 or a protected derivative thereof, for example a 4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl group, 9- borabicyclo[3.3.1]nonane (9-BBN), -Sn(alkyl) 3 (e.g. -SnMe 3 or -SnBu 3 ), or a similar group known to the skilled person, and X 2 is as hereinbefore defined.
  • L 1 and L 2 will be mutually compatible.
  • preferred leaving groups for compounds of formula V in which Q a is -C(O)- include chloro or bromo groups
  • preferred leaving groups for compounds of formula V in which Q a is a single bond include -B(OH) 2 , 4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl, 9-borabicyclo[3.3.1]nonane (9-BBN), or -Sn(alkyl) 3 .
  • This reaction may be performed, for example in the presence of a suitable catalyst system, e.g.
  • a metal such as CuI, Pd/C, PdCl 2 , Pd(OAc) 2 , Pd(Ph 3 P) 2 Cl 2 , Pd(Ph 3 P) 4 , Pd 2 (dba) 3 or NiCl 2 and a ligand such as ⁇ -Bu 3 P, (C 6 Hn) 3 P, Ph 3 P, AsPh 3 , P(O-ToI) 3 , l,2-bis(diphenylphos ⁇ hino)- ethane, 2,2'-bis(di-tert-butylphosphino)-l,l'-biphenyl, 2,2'-bis(diphenyl- phosphino)-l,l'-bi-naphthyl, l,r-bis(diphenyl-phosphinoferrocene), 1,3- bis(diphenylphosphino)propane, xantphos, or
  • reaction may also be carried out for example at room temperature or above (e.g. at a high temperature such as the reflux temperature of the solvent system) or using microwave irradiation.
  • room temperature e.g. at a high temperature such as the reflux temperature of the solvent system
  • microwave irradiation e.g. at a high temperature such as the reflux temperature of the solvent system
  • certain compounds of formula IV in particular those in which L 1 represents chloro, bromo or iodo
  • L 1 represents chloro, bromo or iodo
  • This reaction may be performed under suitable conditions known to those skilled in the art, for example in the presence of a suitable Lewis acid (e.g. AlCl 3 or FeCl 3 ).
  • a suitable Lewis acid e.g. AlCl 3 or FeCl 3
  • Reaction of a compound of formula V in which L represents -N(C 1-6 alkyl) 2 and X 2 represents optionally substituted aryl (e.g. phenyl) or heteroaryl may be performed in the presence of a reagent such as POCl 3 , for example under reaction conditions described in Bioorg. Med. Chem. Lett, 14, Al Al-Al A5 (2004).
  • POCl 3 may convert the compound of formula V into one in which L represents chloro and/or Q a represents a derivative of -C(O)- (e.g. an iminium derivative), which group may be transformed back to a -C(O)- group before or after reaction with the compound of formula I in which X 1 represents H;
  • X lb represents -N(R 9a )-J-R 10a or -Q-X 2 in which Q represents -O- or -S- and R 9a , J, R 1Oa and X 2 are as hereinbefore defined, for example under reaction conditions such as those hereinbefore described in respect of either process (i) or (ii) above;
  • reaction of a compound of formula VI in which X lb represents -Q-X 2 , Q represents -S- and X 2 represents an optionally substituted aryl (phenyl) or heteroaryl (e.g. 2-pyridyl) group may be performed in the presence of PIFA (PhI(OC(O)CF 3 ) 2 ) in a suitable solvent such as (CF 3 ) 2 CHOH.
  • PIFA PhI(OC(O)CF 3
  • a suitable solvent such as (CF 3 ) 2 CHOH.
  • R 1 , R 2 , R 3 , R 4 , R 5 ,T and Y are as hereinbefore defined under reductive amination conditions in the presence of a compound of formula VIII
  • R lla and R 12a are as hereinbefore defined, under conditions well known to those skilled in the art;
  • X 2b represents H, G 1 or Ci -6 alkyl optionally substituted with one or more s ⁇ bstituents selected from G 1 and/or Z 1 and G 1 and Z are as hereinbefore defined, for example, in the case of a reaction of a compound of formula IV with compound of formula IXA, in the presence of an appropriate catalyst (such as PdCl 2 (PPh 3 ) 2 ), a suitable base (e.g. NaOAc and/or triethylamine) and an organic solvent (e.g. DMF) and, in the case of reaction of a compound of formula VII with either a compound of formula EXB, or IXC, under standard Homer- Wadsworth-Emmons, or Wittig, reaction conditions, respectively;
  • an appropriate catalyst such as PdCl 2 (PPh 3 ) 2
  • a suitable base e.g. NaOAc and/or triethylamine
  • organic solvent e.g. DMF
  • L 3 represents L 1 or L 2 as hereinbefore defined, which group is attached to one or more of the carbon atoms of the benzenoid ring of the indole
  • R 2 -R 5 represents whichever of the three other substituents on the benzenoid ring, i.e. R , R 3 , R 4 and R 5 , are already present in that ring
  • X 1 , R 1 , R 2 , R 3 , R 4 , R 5 , T and Y are as hereinbefore defined, with, a compound of formula XI 5
  • L 4 represents L 1 (when L 3 is L 2 ) or L 2 (when L 3 is L 1 )
  • L 1 , L 2 , E 5 R 7 and R 8 are as hereinbefore defined.
  • the reaction may be performed for example under similar conditions to those described hereinbefore in respect of process step (ii) above. Further, the reaction may be performed by first activating the compound of formula X.
  • the skilled person will appreciate that compounds of formula X may first be activated when L 3 represents halo, by:
  • magnesium of the Grignard reagent or the lithium of the lithiated species may be exchanged to a different metal (i.e. a transmetallation reaction may be performed), for example to zinc (e.g. using
  • L represents a silicon-based group such as 1Ii-C 1-6 alkyl silane (e.g. trimethyl silane; for example in the presence of a suitable solvent such as THF), or an alkali metal-based group such as a magnesium halide or lithium (for example at low temperatures (e.g. below 0 0 C) in the presence of a polar aprotic solvent such as THF) and R 7 is as hereinbefore defined, all under standard reaction conditions, following by, in the case of reaction with a silicon-based group, removal of the silicon-based group, under standard conditions known to those skilled in the art (e.g.
  • tetrabutylammonium fluoride optionally in the presence of an appropriate solvent such as THF
  • a reagent that is a source of protons e.g. water or saturated ammonium chloride solution
  • R aa represents R a or R d (as appropriate) provided that it does not represent H, under standard conditions known to those skilled in the art.
  • R aa represents R a or R d (as appropriate) provided that it does not represent H, under standard conditions known to those skilled in the art.
  • a suitable base and an appropriate solvent and under conditions such as those described hereinafter in respect of preparation of compounds of formula I (process step (xiv));
  • reaction of a corresponding compound of formula I in which R represents -OH which first comprises the step of converting the -OH group to provide a suitable leaving group, such as a sulfonate group (e.g. tosyl chloride, mesyl chloride, triflic anhydride and the like) and then reaction with a compound of formula XIVA,
  • a suitable leaving group such as a sulfonate group (e.g. tosyl chloride, mesyl chloride, triflic anhydride and the like)
  • Z a represents either -N(R b )(R c ) or -SR d , under standard conditions known to those skilled in the art;
  • J, R 1Oa and L 1 are as hereinbefore defined, 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, l,8-diazabicyclo[5.4.0]undec-7-ene, sodium hydroxide, or mixtures thereof), an appropriate solvent (e.g.
  • a suitable base e.g. pyrrolidinopyridine, pyridine, triethylamine, tributylamine, trimethylamine, dimethylaminopyridine, diisopropylamine, l,8-diazabicyclo[5.4.0]undec-7-ene, sodium hydroxide, or mixtures thereof
  • an appropriate solvent e.g.
  • xv for compounds of formula I in which X 1 represents -N(R 9a )-J-R 1Oa , J represents a single bond and R 1Oa represents a C 1-8 alkyl group, reduction of a corresponding compound of formula I, in which J represents -C(O)- and R 1Oa represents H or a C 1-7 alkyl group, in the presence of a suitable reducing agent.
  • a suitable reducing agent may be an appropriate reagent that reduces the amide group to the amine group in the presence of other functional groups (for example an ester or a carboxylic acid).
  • Suitable reducing agents include borane and other reagents known to the skilled person;
  • N-bromosuccinimide, bromine or 1,2-dibromotetrachloroethane may be employed, for iodide atoms, iodine, diiodoethane, diiodotetrachloroethane or a mixture of
  • NaI or KI and iV-chlorosuccinimide may be employed, for chloride atoms, N- chlorosuccinimide may be employed and for fluoride atoms, l-(chloromethyl)-4- fiuoro-l,4-diazoniabicyclo[2.2.2]octane bis(tetrafiuoroborate), 1-fluoropyridinium triflate, xenon difluoride, CF 3 OF or perchloryl fluoride may be employed.
  • This reaction may be carried out in a suitable solvent (e.g. acetone, benzene or dioxane) under conditions known to the skilled person;
  • L 5 represents an appropriate alkali metal group (e.g. sodium, potassium or, especially, lithium), a -Mg-halide, a zinc-based group or a suitable leaving group such as halo or -B(OH) 2 , or a protected derivative thereof (the skilled person will appreciate that the compound of formula XVII in which L 5 represents an alkali metal (e.g. sodium, potassium or, especially, lithium), a -Mg-halide, a zinc-based group or a suitable leaving group such as halo or -B(OH) 2 , or a protected derivative thereof (the skilled person will appreciate that the compound of formula XVII in which L 5 represents an alkali metal (e.g.
  • a Mg-halide or a zinc-based group may be prepared from a corresponding compound of formula XVII in which L 5 represents halo, for example under conditions such as those hereinbefore described in respect of preparation of compounds of formula I (process step (x) above)), and X 1 , R 1 , R 2 , R 3 , R 4 and R 5 are as hereinbefore defined, with a compound of formula XVIII,
  • T a represents T and Y a represents Y, provided that when Y represents -C(O)OR 9b , -S(O) 3 R 90 , -P(O)(OR 9d )2, -P(O)(OR 9e )N(R 10f )R 9f 5 -P(O)(N(R 10g )R 9 ⁇ ) 2 , -B(OR 9h ) 2 or -S(O) 2 N(R 10i )R 9i , R 9b to R 9i , R 1Of , R 1Og and R 10i are other than H, and L 6 represents a suitable leaving group known to those skilled in the art, such as halo (especially chloro or bromo), for example when Y a represents -C(O)OR 9b or -S(O) 3 R 90 , or C 1-3 alkoxy, for example when Y a represents -B(OR 9h ) 2 .
  • the reaction may be performed under
  • R 9j represents hydrogen
  • reaction of a corresponding compound of formula I in which T represents a C 2 alkylene group substituted at the carbon atom that is attached to the indole ring system by Z 1 , in which Z 1 represents 0 and Y represents -C(O)OR 9b , in which R 9b represents C 1-6 alkyl with hydroxylamine or an acid addition salt thereof, for example in the presence of base (e.g. NaOH), e.g. under similar reaction conditions to those described in inter alia J. Med. Chem. 43, 4930 (2000);
  • base e.g. NaOH
  • R 9k and R 9r represent hydrogen, reaction of a corresponding compound of formula I in which T represents a Ci alkylene group substituted with G 1 , in which G 1 represents -A ⁇ R 11 ", A 1 represents -C(O)A 2 -, A 2 represents a single bond and R lla represents H, and Y represents -C(O)OR 9b , in which R 9b represents methyl, or ethyl, respectively, with hydroxylamine or an acid addition salt thereof, for example in the presence of base (e.g. NaOH, or aniline, respectively) and an appropriate solvent (e.g. methanol, or water, respectively), e.g. under similar reaction conditions to those described in J. Med. Chem. 44, 1051 (2001), or inter alia J. Am. Chem. Soc, 58, 1152 (1936), respectively;
  • base e.g. NaOH, or aniline, respectively
  • solvent e.g. methanol, or water, respectively
  • R 9m and R 9 * 1 represent hydrogen
  • L 6 preferably represents e.g. a halo group, such as Br, or I, respectively, or a protected derivative (e.g. at the OH group with, for example, a benzyl group) of either compound, for example under reaction conditions similar to those described hereinbefore in process (ii) above and/or in Heterocycles, 36, 1803 (1993), or in Bioorg. Med. Chem., 11, 1883 (2003), respectively, followed by (if necessary) deprotection under standard conditions;
  • X 1 , R 1 , R 2 , R 3 , R 4 and R 5 are as hereinbefore defined with ethoxycarbonyl isocyanate in the presence of a suitable solvent (e.g. dichloromethane), followed by refiuxing in the presence of Triton B and an alcoholic solvent (e.g. methanol), for example under similar reaction conditions to those described in J. HeL Chem., 19, 971 (1982);
  • a suitable solvent e.g. dichloromethane
  • Triton B and an alcoholic solvent e.g. methanol
  • R 9s represents hydrogen
  • X 1 , R 1 , R 2 , R 3 , R 4 and R 5 are as hereinbefore defined with a base (e.g. NaH) and CS 2 in the presence of a suitable solvent (e.g. tetrahydrofuran), oxidation of the resultant intermediate in the presence of, for example, hydrogen peroxide, and finally heating the resultant intermediate in the presence of a strong acid, such as HCl, for example under similar reaction conditions to those described in inter alia Bioorg. Med. Chem. Lett., 2, 809 (1992);
  • a base e.g. NaH
  • a suitable solvent e.g. tetrahydrofuran
  • R 9u represents hydrogen
  • reaction of a compound of formula XIX as hereinbefore defined with 3,4-dimethoxycyclobutene-l,2-dione for example in the presence of base (e.g. KOH) and an appropriate solvent (e.g. methanol), followed by acid (e.g. aqueous HCl), e.g. under similar reaction conditions to those described in J. Org. Chem. , 68, 9233 (2003);
  • base e.g. KOH
  • an appropriate solvent e.g. methanol
  • acid e.g. aqueous HCl
  • X 1 , R 1 , R 2 , R 3 , R 4 and R 5 are as hereinbefore defined with NaN 3 under standard conditions; (xxix) for compounds of formula I in which T represents optionally substituted C 2-8 alkenylene or C 2-8 heteroalkylene (in which a point of unsaturation is between the carbon atoms that are ⁇ and ⁇ to the indole ring), reaction of a compound of formula XXII,
  • T a represents a single bond or optionally substituted C 1-6 alkylene or C 2-6 heteroalkylene and Y is as hereinbefore defined, for example under standard Wittig reaction conditions, e.g. in the presence of a suitable organic solvent (e.g. DMF);
  • a suitable organic solvent e.g. DMF
  • T represents optionally substituted, saturated C 2-8 alkylene, saturated cyclo alkylene, saturated C 2-8 heteroalkylene, saturated heterocycloalkylene, C 2-8 alkenylene, cycloalkenylene, C 2-8 heteroalkenylene or heterocycloalkenylene, reduction (e.g.
  • R 9b to R 9e and R 9h do not represent H (and does not represent the same value of the corresponding R 9b to R 9e and R 9h group in the compound of formula I to be prepared), under standard conditions in the presence of the appropriate alcohol of formula XXIII,
  • R 9za represents R 9b to R 9e or R 9h provided that it does not represent H
  • R 9bl represents R 9b provided that it does not represent H
  • L 6 is as hereinbefore defined (e.g. L 6 represents chloro or bromo), under conditions known to those skilled in the art;
  • R 9b OH XXIIIC wherein R 9b is as hereinbefore defined, and an appropriate catalyst system (e.g. a palladium catalyst such as one described hereinbefore in respect of process step (ii)) under conditions known to those skilled in the art;
  • an appropriate catalyst system e.g. a palladium catalyst such as one described hereinbefore in respect of process step (ii)
  • L 7 represents a suitable leaving group, such as a halo or sulfonate group
  • X 2 is as hereinbefore defined, for example in the presence of a base or under reaction conditions such as those described hereinbefore in respect of process (ii) or process (xiii) above;
  • G 1 substituent in which G 1 represents -A ⁇ R 1 la , A 1 represents -OA 5 -, A 5 represents a single bond and R lla represents H, reaction of a corresponding compound of formula I in which X 2 represents C 1-7 alkyl substituted (e.g. ⁇ to the indole ring) by a Z 1 group in which Z 1 represents 0, with the corresponding Grignard reagent derivative of a compound of formula V in which L 2 represents chloro, bromo or iodo, Q a is a single bond and X 2 represents C 1-7 alkyl, under conditions known to those skilled in the art;
  • -Q-X and Q represents a single bond or -C(O)-, a compound of formula V as hereinbefore defined;
  • G 1 represents -A'-R 113 , A 1 represents -N(R 12a )A 4 -, A 4 is a single bond and R lla and R 12a are preferably methyl, reaction of a corresponding compound of formula II in which X 1 represents H, with a mixture of formaldehyde (or equivalent reagent) and a compound of formula VIII as hereinbefore defined, for example under reaction conditions similar to those described hereinbefore in respect of preparation of compounds of formula I (process (viia)) above;
  • reaction of a corresponding compound of formula II in which R 8 represents -OH which first comprises the step of converting the -OH group to provide a suitable leaving group, such as a sulfonate group (e.g. tosyl chloride, mesyl chloride, triflic anhydride and the like) and then reaction with a compound of formula XIVA as hereinbefore defined;
  • a suitable leaving group such as a sulfonate group (e.g. tosyl chloride, mesyl chloride, triflic anhydride and the like)
  • PG represents a suitable protecting group, such as
  • R 9j represents hydrogen
  • reaction of a corresponding compound of formula II in which T represents a C 2 alkylene group substituted at the carbon atom that is attached to the indole ring system by Z 1 , in which Z 1 represents 0 and Y represents -C(O)OR 9b , in which R 9b represents C 1-6 atkyl with hydroxylamine or an acid addition salt thereof, for example under reaction conditions similar to those described hereinbefore in respect of preparation of compounds of formula I (process (xx)) above;
  • R 9 and R 9r represent hydrogen
  • reaction of a corresponding compound of formula II in which T represents a C 1 alkylene group substituted with G 1 in which G 1 represents -A ⁇ R 11 * 1 ,
  • a 1 represents -C(O)A 2 -
  • a 2 represents a single bond and R lla represents H
  • Y represents -C(O)OR 9b , in which R 9b represents methyl, or ethyl, respectively, with hydroxylarnine or an acid addition salt thereof, for example under reaction conditions similar to those described hereinbefore in respect of preparation of compounds of formula I (process (xxi)) above;
  • R 9m and R 9p represent hydrogen
  • L 6 preferably represents e.g. a halo group, such as Br, or I, respectively, or a protected derivative (e.g. at the OH group with, for example, a benzyl group) of either compound, for example under reaction conditions similar to those described hereinbefore in respect of preparation of compounds of formula I (process (xxii)) above;
  • R 9s represents hydrogen
  • reaction of the resultant intermediate with N 4 S 4 for example under reaction conditions similar to those described hereinbefore in respect of preparation of compounds of formula I (process (xxiv)) above;
  • X 1 , R 2 , R 3 , R 4 and R 5 are as hereinbefore defined with a base (e.g. NaH) and CS 2 the presence of a suitable solvent (e.g. tetrahydrofuran), oxidation of the resultant intermediate in the presence of, for example, hydrogen peroxide, and finally heating the resultant intermediate in the presence of a strong acid, such as
  • R 9u represents hydrogen
  • T represents optionally substituted, saturated C 2-8 alkylene, saturated cycloalkylene, saturated C 2-8 heteroalkylene, saturated heterocycloalkylene, C 2 - 8 alkenylene, cycloalkenylene, C 2-8 heteroalkenylene or heterocycloalkenylene, reduction (e.g. hydrogenation) of a corresponding compound of formula II in which T represents optionally substituted C 2-8 alkenylene, cycloalkenylene, C 2-8 heteroalkenylene, heterocycloalkenylene, C 2-8 alkynylene, cycloalkynylene, C 2-8 heteroalkynylene or heterocycloalkynylene (as appropriate);
  • R 9b , R 9c , R 9d or R 9h does not represent H, or, for compounds of formula II in which Y represents -P(O)(OR 9d ) 2 or S(O) 3 R 90 , in which R 9 ° and R 9d represent H, a corresponding compound of formula II in which Y represents either -P(O)(OR 9e )N(R 10f )R 9f , -P(O)(N(R 10g )R 9g ) 2 or -S(O) 2 N(R 10i )R 9i (as appropriate);
  • PG represents a suitable protecting group, such as -S(O) 2 Ph, -C(O)O " , -C(O)OtBu or -C(O)N(Et) 2 ) and L 5 , Q, X 2 , R 2 , R 3 , R and R 5 are as hereinbefore defined, with a compound of formula XXIIIB as hereinbefore defined, for example under reaction conditions similar to those described hereinbefore in respect of preparation of compounds of formula I (process (xxxiii)) above), followed by deprotection of the resultant compound under standard conditions;
  • R 1 and L 2 are as hereinbefore defined or a compound of formula III as hereinbefore defined, for example under reaction conditions similar to those described hereinbefore in respect of preparation of compounds of formula I (processes (ii) and (i), respectively) above; or
  • Compounds of formula VII may be prepared by: (a) for compounds of formula VII in which D represents a single bond, -C(O)-, -C(R 7 XR 8 )-, C 2-4 alkylene or -S(O) 2 -, reaction of a compound of formula XXXVIII,
  • Compounds of formula X may be prepared by reaction of a compound of formula XXVIII as hereinbefore defined, with a compound of formula III as hereinbefore defined, for example under reaction conditions similar to those described hereinbefore in respect of preparation of compounds of formula I (process (i)) above.
  • R 9a is as hereinbefore defined, for example under reaction conditions similar to those described hereinbefore in respect of preparation of compounds of formula I (process (ii)) above).
  • R z represents R 1 (in the case of a compound of formula XVII) or PG (in the case of a compound of formula XXXI), and PG, X 1 , R 1 , R 2 , R 3 , R 4 and R 5 are as hereinbefore defined, with an appropriate base, such lithium diisopropylamide or BuLi under standard conditions.
  • Compounds of formulae XVII and XXXI in which L 5 represents -Mg-halide may be prepared from a corresponding compound of formula XVII or XXXI (as appropriate) in which L 5 represents halo, for example under conditions such as those described hereinbefore in respect of process step (x).
  • Compounds of formulae XVII and XXXI in which L 5 represents, for example, a zinc-based group, or a halo or boronic acid group a group (such as a zinc-based group, halo or a boronic acid) may be prepared by reacting a corresponding compound of formula XVII or XXXI in which L 5 represents an alkali metal with an appropriate reagent for introduction of the relevant group, for example by a metal exchange reaction (e.g.
  • a Zn transmetallation by reaction with a suitable reagent for the introduction of a halo group (for example, a reagent described hereinbefore in respect of preparation of compounds of formula I (process (xvi)) or, for the introduction of a boronic acid group, reaction with, for example, boronic acid or a protected derivative thereof (e.g. bis(pinacolato)diboron or triethyl borate) followed by (if necessary) deprotection under standard conditions.
  • a suitable reagent for the introduction of a halo group for example, a reagent described hereinbefore in respect of preparation of compounds of formula I (process (xvi)
  • a boronic acid group reaction with, for example, boronic acid or a protected derivative thereof (e.g. bis(pinacolato)diboron or triethyl borate) followed by (if necessary) deprotection under standard conditions.
  • R 1 , R 2 , R 3 , R 4 and R 5 are as hereinbefore defined, with an appropriate reagent known to be a suitable source of halide atoms (see for example process (xvi) above in respect of preparation of compounds of formula I).
  • Compounds of formulae XX and XXXIII, and XXII and XXXV may be prepared by reduction of a corresponding compound of formula I, or of formula II, respectively, in which T represents a single bond and Y represents -C(O)OR 9b , to the corresponding primary alcohol (using e.g.
  • Compounds of formulae XXI and XXXTV may be prepared by conversion of a corresponding compound of formula I which T represents a single bond and Y represents -C(O)OR 9b to the corresponding primary amide (e.g. when R 9b is H, by reaction with SOCl 2 followed by ammonia or when R 9b is other than H, by reaction with ammonia), followed by dehydration of the resultant intermediate in the presence of a suitable dehydrating agent, such as POCl 3 , in all cases under reaction conditions that will be well known to those skilled in the art.
  • a suitable dehydrating agent such as POCl 3
  • Compounds of formulae XXVII and XXXVIII, in which Q represents a single bond and X 2a represents -CHO, may be prepared from compounds of formulae II, or X, respectively, in which X 1 represents H, by reaction with a mixture of DMF and, for example, oxalyl chloride, phosgene or P(O)Cl 3 (or the like) in an appropriate solvent system (e.g. DMF or dichloromethane) for example as described hereinbefore.
  • an appropriate solvent system e.g. DMF or dichloromethane
  • Indoles of formulae II, IV 5 VII, X, XIII 5 XV 5 XVII, XIX, XX, XXI, XXII, XXIIIA, XXIV, XXVI 5 XXVII, XXVIII, XXIX, XXX, XXXI, XXXIII, XXXTV, XXXV 5 XXXVA, XXVI, XXVIII, XL, XLI and XLII may also be prepared with reference to a standard heterocyclic chemistry textbook (e.g. "Heterocyclic Chemistry" by J. A. Joule, K.
  • SUB represents the substitution pattern that is present in the relevant compound to be formed (in this case, the compound of formula II, XXVIII or XXIX, respectively)
  • X y represents H, -N(R 9a )- J-R 1Oa or -Q-X 2
  • R 9a , R 1Oa , J 5 Q, X 2 , T and Y are as hereinbefore defined, under Fischer indole synthesis conditions known to the person skilled in the art.
  • T is as hereinbefore defined and preferably a single bond or optionally substituted arylene or heteroarylene
  • Y is as hereinbefore defined and, when T represents a single bond, preferably represents -C(O)OR 9b in which R 9b preferably does not represent hydrogen, under conditions known to the person skilled in the art (i.e. conditions to induce a condensation reaction, followed by a thermally induced cyclisation).
  • R x represents a C 1-6 alkyl group
  • R y represents either R (as required for the formation of compounds of formula XXIV), hydrogen (as required for the formation of compounds of formula XXXVI) or a nitrogen-protected derivative thereof
  • R 1 , R 2 , R 3 , R 4 , R 5 , T and Y are as hereinbefore defined for example under cyclisation conditions known to those skilled in the art.
  • SUB, T and Y are as hereinbefore defined, for example under intramolecular cyclisation conditions known to those skilled in the art.
  • V represents either -C(O)- or -CH 2 -
  • X z represents H, -N(R 9 ⁇ -J-R 1 Oa or -Q-X 2 in which Q represents a single bond or -C(O)- and SUB, R 9a , R 1Oa , J 5 T and
  • V represents -C(O)-
  • the intramolecular cyclisation may be induced by a reducing agent such as TiCl 3 /C 8 K, TiCL/Zn or
  • R m represents OH, 0-C 1-6 alkyl or C 1-6 alkyl and X y , T and Y are as hereinbefore defined, for example under Japp-Klingemann conditions known to the skilled person.
  • T, Y and V are as hereinbefore defined, under standard coupling conditions.
  • the substituents X 1 , R 1 , R 2 , R 3 , R 4 , R 5 , T and Y 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.
  • the protection and deprotection of functional groups may take place before or after a reaction in the above-mentioned schemes.
  • Protecting groups may be removed in accordance with techniques that are well known to those skilled in the art and as described hereinafter. For example, protected compounds/intermediates described herein may be converted chemically to unprotected compounds using standard deprotection techniques.
  • compounds of the invention may 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 of the invention that possess pharmacological activity as such (including, but not limited to, corresponding compounds of formula I 5 in which R 9b represents hydrogen).
  • 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.
  • 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 may inhibit the activity of leukotriene C 4 (LTC 4 ) synthase, for example as may be shown in a test such as that described in Eur. J. Biochem., 208, 725-734 (1992), and may thus be useful in the treatment of those conditions in which inhibition of LTC 4 is required.
  • Compounds of the invention may also inhibit the activity of 5-lipoxygenase-activating protein (FLAP), for example as may be shown in a test such as that described in MoI. Pharmacol., 41, 873-879 (1992).
  • FLAP 5-lipoxygenase-activating protein
  • 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 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.
  • a pharmaceutical formulation including a compound of the invention, as hereinbefore defined, 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, 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:
  • 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;
  • kit of parts comprising components: (a) a pharmaceutical formulation including a compound of the invention, as hereinbefore defined, in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier; and
  • 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 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:
  • 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/da ⁇ '.
  • 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.
  • Biological Test e.g. higher oral bioavailability and/or lower clearance
  • 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
  • the assay is performed at room temperature in 96-well plates. Analysis of the amount of PGE 2 is performed with reversed phase HPLC (Waters 2795 equipped with a 3.9 x 150 mm C18 column). The mobile phase consists OfH 2 O / MeCN (7/3), containing TFA (0.056%), and absorbance is measured at 195 nm with a Waters 2487 UV-detector.
  • Example 1 The compound of Example 1 was tested in the biological test described above and was found to exhibit 50% inhibition of mPGES-1 at a concentration of 10 ⁇ M or below.

Abstract

L'invention concerne des composés de formule (I), dans laquelle X1, R1, R2, R3, R4, R5, T et Y sont tels que définis dans la description, ainsi que des sels pharmaceutiquement acceptables de ces composés. Lesdits composés 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 notamment dans le traitement de l'inflammation.
PCT/GB2007/002704 2006-07-18 2007-07-18 Indoles utiles dans le traitement de l'inflammation WO2008009924A2 (fr)

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