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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 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 cardio avascular 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 broncho constriction. 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 disease 0
• COX cyclo oxygenase
• 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 2Ct , PGD 2 , prostacyclin and thromboxane A 2 .
• PGE 2 metabolise arachidonic acid to the unstable intermediate prostaglandin H 2 0
• PGD 2 oxidation factor 2
• prostacyclin thromboxane A 2
• These arachidonic acid metabolites 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 O reducing the formation of P GE 2 .
• the inhibition of COXs has the disadvantage that it results in the reduction of the formation of all metabolites of arachidonic acid, some of which are known to have beneficial properties. In 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 B4 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 broncho constrictors and have thus been implicated in the pathobiology of asthma.
• the biological activities of the CysLTs are mediated through two receptors designated CysLTj 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 CysLTi. 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.
• Indole-2-carboxylates, and derivatives thereof, are disclosed in international patent applications WO 2005/005415, WO 2005/123675, WO 2005/123673 and WO 2005/123674 for use as inhibitors of mPGES and thus in the treatment of inflammation.
• Thienopyrroles are neither mentioned nor suggested in any of these documents.
• International patent application WO 2004/022537 discloses tMenopyrrol-5-yl-(4- methyrpiperazinyl-l-yl)methanone derivatives for use in the treatment of diseases mediated by the histamine HU receptor.
• this document does not disclose compounds with aromatic substituents attached to the ring system via the pyrrole nitrogen.
• one of U and V represents -S- and the other represents -C(R 3 )-;
• R 2 and R J represents -D-E and the other represents H, halo, -NO 2 , cyano or Cj -6 alkyl, which alkyl group is optionally substituted by one or more substituents selected from halo, hydroxy and Ci -6 alkoxy;
• D represents a single bond, -O-, -C(R 6 )(R 7 )- 5 C 2-4 alkylene, -C(O)- or -S(O) m -;
• R 1 represents an aryl group or a heteroaryl group, both of which groups are optionally substituted by one or more substituents selected from A;
• E represents either an aryl or heteroaryl group (both of which groups are optionally substituted by one or more substituents selected from A), or a heterocycloalkyl group (which group is optionally substituted by one or more substituents selected from G 1 and/or Z 1 );
• R 6 and R 7 independently represent H 5 halo or Cj -6 alkyl, which latter group is optionally substituted by halo, or R 6 and R 7 may together form, along with the carbon atom to which they are attached, a 3- to 6-membered ring, which ring optionally contains a heteroatom and is optionally substituted by one or more substituents selected from halo and Ci -3 alky L which latter group is optionally substituted by one or more halo substituents;
• X 1 represents H, halo, -N(R>J-R y or -Q-X z ;
• J represents a single bond, -C(O)- or -S(O) m -;
• Q represents a single bond, -O-, -C(O)- or -S(O) 111 -;
• n represents, on each occasion when mentioned above, 0, 1 or 2;
• 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
• Y represents a single bond, or a C 1-8 alkylene or C 2- S heteroalkylene chain, both of which latter two groups:
• R 8 , R 9 , R 1Oa to R lof , R l lb , R lle , R 12a , R 12b and R I3b independently represent, on each occasion when mentioned above: I) hydrogen;
• C 1-S 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 R 8 and R 9 , R 1Ob and R l lb , R 1Oe and R lle , and R 12b and R 13b (as appropriate), may be linked together to form, along with the N atom and (in the case of R 9 ) the J group to which they are attached, a 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 1 and/or Z 1 ;
• A represents, on each occasion when mentioned above:
• G 1 represents, on each occasion when mentioned above, halo, cyano, -N 3 ,
• a 1 represents a single bond or a spacer group selected from
• a 2 represents a single bond, -O-, -N(R I5b > or -C(O)-;
• a 3 represents a single bond, -O- or -N(R I5c )-;
• a 4 and A 5 independently represent a single bond, -C(O)-, -C(0)N(R 15d >, -C(O)O-, -S(O) 2 - or -S(O) 2 N(R 156 )-;
• B represents, on each occasion when mentioned above: 1) an aryl group or a heteroaryl group, both of which are optionally substituted by one or more substituents selected from G 2 ;
• Ci-S alkyl or a heterocycloalkyl group both of which are optionally substituted by one or more substituents selected from G 2 and/or Z 2 ; or
• G represents, on each occasion when mentioned above, halo, cyano, -N 3 , -NO 2 , -ONO 2 or -A 6 -R 16a ; wherein A 6 represents a single bond or a spacer group selected from -C(O)A 7 -, -S(O) 2 A 8 -, -N(R 17a )A 9 - or -OA 10 -, in which: A 7 represents a single bond, -0-, -N(R 17b )- or -C(O)-; A 8 represents a single bond, -O- or -N(R 17c )-;
• a 9 and A 10 independently represent a single bond, -C(O)-, -C(0)N(R 17d >, -C(O)O-, -S(O) 2 - or -S(O) 2 N(R 176 )-;
• R 17d , R 17e and R 17f 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- S alkyl or a heterocycloalkyl group, both of which are optionally substituted by one or more substituents selected from G 3 and/or Z 3 ; or any pair of R 14a to R 14c and R 15a to R 15f , and/or R 16a to R 16c and R 17a to R 17f , 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 , -ONO 2 or -A ⁇ -R 18a ; wherein A 11 represents a single bond or a spacer group selected from -C(O)A 12 -, -S(O) 2 A 13 -, -N(R 19a )A 14 - or -OA 15 -, in which: A 12 represents a single bond, -0-, -N(R 19b )- or -C(O)-; A 13 represents a single bond, -O- or -N(R 19c )-; A 14 and A 15 independently represent a single bond, -C(O)-, -C(O)N(R 19d >, -C(O)O-, -S(O) 2 - or -S(O) 2 N(R 196 )-;
• R 18a , R 18b , R 18c , R 19a , R 19b , R 19c , R 19d , R 19e and R 19f are independently selected from: i) hydrogen; ii) Ci-6 alkyl or a heterocycloalkyl group, both of which groups are optionally substituted by one or more substituents selected from halo, Ci -4 alley],
• R 18a to R 18c and R 19a to R 19f 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 heteroatoms and/or 1 to 3 double bonds, which ring is optionally substituted by one or more substituents selected from halo, C 14 alkyl, -N(R 2Oe )R 21c , -OR 20f and
• R 2Oa , R 2Ob 3 R 2Oc , R 2Od , R 2Oe , R 2Of , R 21a , R 21b and R 21c are independently selected from hydrogen and C 1-4 alkyl, which latter group is optionally substituted by one or more halo groups;
• V represents S
• D represents -C(O)-
• E represents phenyl
• X 1 represents -Q-X 2
• Q represents a single bond
• R 3 and X 2 both represent methyl
• R 4 represents ethoxy
• Y represents a single bond
• R 1 does not represent an unsubstituted phenyl group
• 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 (ent ought) 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 exhibit tautomerism. AU tautomeric forms 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 5 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, the alkyl part of C 1-q alkoxy, and Ci -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 cyclic (so forming, in the case of alkyl, 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.
• C 3-q cycloalkyl groups (where q is the upper limit of the range) that may be mentioned 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 bonds (forming for example a C 3 _ q cycloalkenyl or a Cs -q cycloalkynyl group). 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.
• C 2-S heteroalkylene chains include C 2-8 alkylene chains that are interrupted by one or more heteroatom groups selected from -O-, -S- or -N(R 24 )-, in which R 24 represents C M alkyl, optionally substituted by one or more halo (e.g. fluoro) groups.
• R 24 represents C M alkyl, optionally substituted by one or more halo (e.g. fluoro) groups.
• halo when used herein, includes fluoro, chloro, bromo and iodo.
• Heterocycloalkyl groups that may be mentioned include non-aromatic monocyclic and bicyclic groups 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 hetero cycloalkenyl
• C 2-q hetero cycloalkyl 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-
• heterocycloalkyl 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 "spiro"-compound.
• heterocyclo alley 1 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.
• 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-I3 (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-J4 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 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 S ⁇ -dihydro ⁇ //-! ⁇ - benzoxazinyl), benzoxazolyl, benzomorpholinyl, benzoselenadiazolyl (including 2,1,3-benzoselenadiazolyl), benzothienyl, carbazolyl, chromanyl, cinnolinyl, furanyl, imidazolyl, imi
• heteroaryl groups may, where appropriate, be located on any atom in the ring system including a heteroatom.
• the point of attachment of heteroaiyl groups may be via any atom in the ring S5'stem 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 N- or S- oxidised form.
• Heteroatoms that may be mentioned include phosphorus, silicon, boron, tellurium, selenium and, preferably, oxygen, nitrogen and sulphur.
• the identity of two or more substituents in a compound of the invention may be the same, the actual identities of the respective substituents are not in any way interdependent.
• the alkyl groups in question may be the same or different.
• groups are substituted by more than one substituent as defined herein, the identities of those individual substituents are not to be regarded as being interdependent.
• X 2 and/or R 1 represents e.g. an aryl group substituted b ⁇ G 1 in addition to, for example, C 1-8 alley 1, which latter group is substituted by G 1 , the identities of the two G 1 groups are not to be regarded as being interdependent.
• E represents an optionally substituted heterocycloalkyl group
• it is a C 4-5 heterocyclo alley 1 group (which group is preferably a nitrogen-containing heterocycloalkyl group, optionally containing a further nitrogen and/or oxygen atom) optionally substituted by one or more (e.g. one) substituents selected from G 1 and/or, preferably, Z 1 .
• Still further compounds of the invention that may be mentioned include those in which E represents an aryl or a heteroaryl group, both of which are optionally substituted by one or more substituents selected from A.
• Preferred compounds of the invention include those in which: A represents G 1 ; an aryl group or a heteroaryl group, both of which are optionally substituted by one or more B groups; a C] -5 alkyl group, which alkyl group is optionally unsaturated and is optionally substituted by one or more G 1 groups;
• X 2 represents optionally substituted aryl or heteroaryl, Ci -6 alkyl or heterocyclo alkyl (which latter two groups are preferably substituted with one or more (e.g.
• R 8 represents H or Ci -2 alkyl (e.g. methyl);
• R 9 represents Cj -6 (e.g. C 1-3 ) alkyl, which group may be unsubstituted, but is preferably substituted by one or more (e.g. one) groups selected from G 1 ; or R 8 and R 9 are linked to form a 4- to 7-membered (e.g. 5- or 6-membered) ring, which ring may, for example preferably, contain (in addition to the nitrogen atom and J group to which R s and R 9 are respectively 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;
• a further heteroatom e.g. nitrogen or oxygen
• R i o a t0 R j o f R iib md R i i e independently represent H or C 1-2 alkyl;
• G 1 represents halo, -NO 2 or -A ⁇ R 14 *
• a 1 represents -N(R 15a )A 4 - or, preferably, a single bond, -C(O)A 2 - or -OA 5 -;
• a 2 represents -O-;
• a 4 and A 5 independently represent a single bond, -C(O)-, -C(O)N(R 15d )- or -C(O)O-;
• a 6 represents -N(R 17a )A 9 - or -OA 10 -;
• a 9 represents -C(0)N(R 17d )-, -C(O)O- or, more preferably, a single bond or
• a 10 represents a single bond
• R 16a to R 16c independently represent Ci -3 alkyl
• G 3 represents halo or -A 1 ⁇ R 183 ;
• a 11 represents a single bond, -OA 15 - or, more preferably, -C(O)A 12 -;
• a 12 represents -O- ;
• a lD represents a single bond, when any one of R 18a , R 18b , R 18c , R I9a , R 19b , R 19c , R 19d , R 19e and R 19f represents optionally substituted C 1-6 alkyl, the optional substituent is one or more halo groups;
• R 18a to R 18c independently represent Ci -4 alkyl, aryl or H;
• J represents a single bond, -C(O)- or -S(O) 2 -; when any one of R 20a , R 20b , R 2Oc , R 20d , R 20e , R 20f , R 21a , R 21b and R 21c represents optionally substituted Ci -4 alkyl, the optional substituent is one or more fluoro groups.
• Preferred aryl and heteroaryl groups that R 1 , X 2 (when X 2 represents an aryl or heteroaryl group) and/or E may represent include optionally substituted phenyl, naphthyl, pyrrolyl, furanyl, thienyl (e.g. thien-2-yl or thien-3-yl), pyrazolyl, imidazolyl (e.g 1-imidazolyl, 2-imidazolyl or 4-imidazo IyI) 5 oxazolyl, isoxazolyl, thiazolyl, pyridyl (e.g.
• Preferred values include phenyl, thienyl, pyridyl and imidazolyl.
• Preferred values of E, when R and/or R represent -D-E include optionally substituted pyridyl, phenyl, thienyl (e.g. 2-thienyl) and imidazolyl.
• R 1 examples include optionally substituted phenyl, thienyl (e.g. 2- tliienyl), pyridyl (e.g. 2-pyridyl and 3-pyridyl) and imidazolyl.
• More preferred compounds of the invention include those in which:
• X 1 represents H, halo (such as iodo, chloro or fluoro) or -Q-X 2 ;
• Q represents -O-, -S- or, more preferably, a single bond;
• X 2 represents an aryl (e.g. phenyl) group or a heteroaryl group, both of which are optionally substituted with one or more A groups as defined herein, or an optionally unsaturated C] -3 alkyl (e.g. methyl or ethynyl) group optionally substituted with one or more G 1 groups;
• A represents G 1 ; a phenyl group, a thienyl (such as a thien-2-yl) group, both of which are optionally substituted by one or more B groups; or a methyl, ethyl, ethenyl, ethynyl or f-butyl group, each of which is optionally substituted by one or more G 1 groups;
• Y represents a C 1-3 alkylene spacer group (such as an ethylene or, preferably, a methylene group) or, more preferably, a single bond; the R or R group (as appropriate) that does not represent -D-E represents H, halo
• Ci -3 alkyl such as methyl
• D represents -C(R 6 )(R 7 )- or, preferably, a single bond or a Cj -3 alkylene (e.g. an ethynylene) linker group; R 6 and R 7 . independently represent H, fluoro or C 1 ⁇ (e.g. . Ci -2 ) alkyl (such as methyl);, or
• R 6 and R 7 are linked together to form a C 3 . 6 (e.g. C 3-4 ) cycloalkyl group;
• R 12a and R 1 independently represent H or Ci -3 alkyL such as methyl; when R 4 represents -N(R 12b )R 13b , R 12b represents H and R 13b represents a C 1-4 alkyl group (e.g. an ethyl group) substituted by G 1 ; when R 4 represents -OR I2a , R 12a represents H;
• G 1 represents fluoro, chloro, -NO 2 or -A ⁇ R 1415 ;
• a 4 and A 3 independently represent a single bond;
• R 14a to R 14c independently represent H, an aryl (e.g. phenyl) group, a heteroaryl (such as tetrazolyl (e.g. 5-tetrazolyl), imidazolyl (e.g. 4-imidazolyl or 2- imidazolyl) or, more preferably, pyridyl (e.g. 2-pyridyl, 3-pyridyl or, especially, A- pyridyl) or thiazolyl (e.g.
• 5-thiazolyl)) group a linear C 1-6 alkyl group (such as a methyl or an ethyl group), an unsaturated C 2-6 alkyl group (such as an ethenyl or an ethynyl group), a branched C 2-6 alkyl group (such as an isopropyl group), or a cyclic C 3-6 alkyl group (such as a cyclopropyl or cyclopentyl group), which latter six groups are optionally substituted with one or more G 3 substituents;
• B represents methyl or G 2 ;
• G 2 represents -A 6 -R 16a ;
• a 6 represents -OA 10 -;
• R 16a to R 1 c independently represent methyl or ethyl;
• G 3 represents fluoro or -A ⁇ -R 18a ;
• a 11 represents -C(O)O-;
• R 1Sa to R 18c independently represent Ci -3 alkyl (such as a methyl group or an ethyl group), a phenyl group or, more preferably, H.
• R 1 , X 2 (when X 2 represents an aryl or heteroaryl group) and E groups are preferably selected from: halo (e.g. fluoro, chloro or bromo); cyano;
• Ci -6 alkyl which alkyl group may be linear or branched (e.g. Ci -4 alkyl (including ethyl, ⁇ -propyl, isopropyl, 77-butyl or, preferably, methyl or f-butyl), 77-pentyl, isopentyl, 77-hexyl or isohexyl), cyclic (e.g. cyclopropjd, cyclobutyl, cyclohexyl or, preferably, cyclopentyl), part-cyclic (e.g. cyclopropjdmethyi), unsaturated (e.g.
• aryl e.g. phenyl
• aryl optionally substituted by one or more halo or. preferably, C 1-4 alkoxy (e.g. ethoxy or isopropoxy) group
• heteroaryl e.g. thienyl, such as thien-2-yl
• 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-piperazinyl) or piperidinyl (e.g. 1-piperidinyl and 4-piperidinyl) or pyrrolidinyl (e.g. 1- pyrrolidinyl), which heterocycloalkyl group is optionally substituted by one or more (e.g. one or two) substituents selected from Ci -3 alkyl (e.g.
• R 22 and R 23 independently represent, on each occasion when mentioned above, H, phenyl or Ci -6 alkyl, such as methyl, ethyl, ⁇ -propyl, isopropyl, /2-butyL f-butyl or cyclopropyl (which alkyl groups are optionally substituted by one or more -CO 2 H groups (so forming e.g. a carboxypropan-2-yl group) or one or more halo (e.g. fluoro) groups (so forming e.g. a trifluoromethyl group)).
• X 2 include C 1-3 alkyl (e.g. methyl), which group is unsubstituted or, preferably, substituted by one or more halo (e.g. fluoro or chloro) groups so forming, for example, a trifluoromethyl group.
• halo e.g. fluoro or 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 and Y are 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 PPh 3 , 2,2'-bis(diphenylphospliino)-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,
• TMs reaction may be carried out at room temperature or above (e.g.
• 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 5 2-dioxaborolan-2-yl group, 9- borabicyclo[3.3.1Jnonane (9-BBN) 5 -Sn(alkyl) 3 (e.g. -SiOMe 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(PPh 3 ) 2 Cl 2 , Pd(PPh 3 ) 4 , Pd 2 (dba) 3 or NiCl 2 and a ligand such as A-Bu 3 P, (C 6 Hn) 3 P, PPh 3 , AsPh 3 , P(O-ToI) 3 , l,2-bis(diphenylphosphino)- ethane, 2,2'-bis(di-rer/'-butylphosphino)-l,l l -biphenyl, 2,2'-bis(diphenyl- phosphino)- 1 , 1 '-binaphthyl, 1 , 1 '-bis(diphenyl-phosphino ferrocene), 1,3- bis(diphenylphosphino)propane, x
• 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 2 represents -N(Ci -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 1 Al-Al '45 (2004).
• POCl 3 may convert the compound of formula V into one in which L 2 represents chloro and/or Q a represents a derivative of -C(O)- (e.g. an minium 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; (iv) for compounds of formula I in which X 1 represents -N(R 8 )-J-R 9 or -Q-X 2 in which Q represents -O- or -S-, reaction of a compound of formula IV as hereinbefore defined with a compound of formula VI,
• X lb represents -N(R 8 )-J-R 9 or -Q-X 2 in which Q represents -O- or -S- and R 8 , J, R 9 and X 2 are as hereinbefore defined, for example under reaction conditions as 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.
• the dotted lines, U, V, R 1 , R 2 , R 4 and Y are as hereinbefore defined under reductive amination conditions in the presence of a compound of formula VIII
• R 1 a and R 15a are as hereinbefore defined, under conditions well known to those skilled in the art;
• a 1 represents -OA 5 - or -N(R 15a )A 4 -, A 4 and A 5 both represent a single bond and R 14a represents hydrogen), reaction of a corresponding compound of formula IV in which L 1 represents halo (e.g. iodo) with a compound of formula IXA,
• X 2b represents H
• G 1 (wherein G 1 is preferably other than -A ⁇ R 143 in which A 1 represents -OA 5 - or -N(R 15a )A 4 -, A 4 and A 5 both represent a single bond and R 14a represents hydrogen) or Ci -6 alkyl optionally substituted with one of more substituents selected from G 1 and/or Z 1 and G 1 and Z 1 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 ) 5 a suitable base (e.g.
• L 3 represents L 1 or L 2 as hereinbefore defined, which group is attached to one or both of the two carbon atoms of the thienoid ring of the thienopyrrole
• R 2 -R 3 represents whichever other substituent on the thienoid ring, i.e. R 2 or R 3 , is already present in that ring
• the dotted lines, U, V, X 1 , R 1 , R 2 , R 3 , R 4 and Y are as hereinbefore defined, with a compound of formula XI,
• D a represents a single bond, -C(O)-, -C(R 6 )(R 7 )-, C 2-4 alkylene or -S(O) 2 -
• L 4 represents L 1 (when L 3 is L 2 ) or L 2 (when L 3 is L 1 ) and L 1 , L 2 , E, R 6 and R 7 are as hereinbefore defined.
• D a represents a single bond, -C(O)- or C 2 ⁇ alkylene
• the reaction may be performed for example under similar conditions to those described hereinbefore in respect of process step (ii) above.
• reaction may be performed by first activating the compound of formula X.
• L represents halo
• magnesium of the Grignard reagent or the lithium of the lithiated species may be exchanged to a different metal (Le. a transmetallation reaction may be performed), for example to zinc (e.g. using ZnCl 2 ) and the intermediate so formed may then be subjected to reaction with a compound of formula XI under conditions known to those skilled in the art, for example such as those described hereinbefore in respect of process (ii) above;
• a suitable catalyst system such as Cu(OAc) 2
• a suitable base such as triethylamine or pyridine
• an appropriate organic solvent such as DMF or dichloromethane
• L is as hereinbefore defined (for example -B(OH) 2 , chloro, bromo or iodo) and E is as hereinbefore defined, for example under conditions such as those described hereinbefore in respect of process step ( ⁇ ) above;
• J, R 9 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) and 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.
• 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; (xvi) for compounds of formula I in which X 1 represents halo, reaction of a compound of formula I wherein X 1 represents H, with a reagent or mixture of reagents known to be a source of halo atoms.
• N- bromosuccinimide, bromine or 1,2-dibromotetrachloroethane may be employed, for I atoms, iodine, diiodoethane, diiodotetrachloroethane or a mixture of NaI or KI and N-cMorosuccinirnide may be employed, for Cl atoms, N-cHorosuccinirnide may be employed and for F atoms, l-(chloromethyl)-4-fluoro-l,4- diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate), 1-fiuoropyridinium trifiate, 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, and the dotted lines, U, V, X , R , R and Y are as hereinbefore defined, with a compound of formula XVIII,
• R 12za represents R 12a provided that it does not represent H 5 and L 6 represents a suitable leaving group such as halo (especially chloro or bromo) under conditions known to those skilled in the art; (xviii) for compounds of formula I in which R 4 represents -OR 12a and R I2a is H, reaction of a compound of formula XVII in which L 5 represents either:
• R 12a 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)
• R 12b and R 13b are as hereinbefore defined under standard conditions.
• the reaction may be performed in the presence of a suitable coupling reagent (e.g. l,r-carbonyld ⁇ rnidazole, ⁇ N'-dicyclohexylcarbodiimide, l-(3- dimethylaminopropyl)-3-ethylcarbo-diimide (or hydrochloride thereof), N,N"- disuccinimidyl carbonate, benzotriazol- 1 -yloxytris(dimethylamino)phosphonium hexafluoro-phosphate, 2-(l //-benzotriazol- 1 -yl)- 1 , 1 ,3,3 -tetramethyluiOnium hexa- fluorophosphate, benzotriazol- 1-yloxytris-pyrrolidrnophosphonium hexa- fluorophosphate, bromotrispyrroli
• n-, s- or f-butyllithium or mixtures thereof
• an appropriate solvent e.g. tetrahydrofuran, pyridine, , toluene, dichloromethane, chloroform, acetonitrile, dimethylformamide, dimethylsulfoxide, water, triethylamine or mixtures thereof.
• an azodicarboxylate may be employed under Mitsunobo conditions known to those skilled in the art.
• oxalyl chloride thionyl chloride, etc
• an appropriate solvent e.g. dichloromethane, THF, toluene or benzene
• a suitable catalyst e.g. DMF
• An alternative way of performing this step includes the reaction of a compound of formula I in which R 4 represents -OR 12a in which R 12a is other than H (e.g. ethyl) with a compound of formula XX, in the presence of, e.g. trimethylaluminium, for example in an inert atmosphere and in the presence of a suitable solvent (e.g. dichloromethane);
• L 7 represents a suitable leaving group, such as a halo or sulfonate group and 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 (xiii) above;
• PG represents a suitable protecting group, such as
• a 1 represents -OA D -
• a 5 represents a single bond and R 14a represents H
• reaction of a corresponding compound of formula II 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;
• R 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 (b) for compounds of formula IV wherein L 1 represents a sulfonate group, reaction of a compound of formula XXI as hereinbefore defined with an appropriate reagent for the conversion of the hydroxyl group to the sulfonate group (e.g. tosyl chloride, mesyl chloride, triflic anhydride and the like) under conditions known to those skilled in the art.
• an appropriate reagent for the conversion of the hydroxyl group to the sulfonate group e.g. tosyl chloride, mesyl chloride, triflic anhydride and the like
• reaction of a compound of formula XXIV 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); or (c) for compounds of formula VII in which Q represents a single bond and X 2a represents -CHO, reaction of a corresponding compound of formula I in which X 1 represents H with a mixture of DMF and, for example, oxalyl chloride, phosgene or P(0)Cl 3 (or the like) in an appropriate solvent system (e.g. DMF or dichloromethane).
• an appropriate solvent system e.g. DMF or dichloromethane
• Compounds of formula X may be prepared by reaction of a compound of formula XXV 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.
• Compounds of formula X in which L 3 represents L 2 may be prepared by reaction of a compound of formula X in which L 3 represents L 1 , with an appropriate reagent for the conversion of the L 1 group to the L group. This conversion may be performed by methods known to those skilled in the art, for example, compounds of formula X, in which L 3 is 4,4,5, 5-tetramethy 1-1,3, 2-dioxaborolan-2- yl may be prepared by reaction of the reagent bis(pinacolato)diboron with a compound of formula X in which L J represents L 1 , 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 -Y-R 1 (in the case of a compound of formula XVII) or PG (in the case of a compound of formula XXVIII), and the dotted lines, U, V, PG, X 1 , Y, R 1 and R 2 are as hereinbefore defined, with an appropriate base, such as lithium diisopropylamide or BuLi under standard conditions.
• Compounds of formulae XVII and XXVIII in which L 5 represents -Mg-halide may be prepared from a corresponding compound of formula XVII or XXVIII (as appropriate) in which V represents halo, for example under conditions such as those described hereinbefore in respect of process step (x).
• Compounds of formulae XVII and XXVIII in which L 5 represents, for example, a zinc-based group, halo or a boronic acid group may be prepared by reacting a corresponding compound of formula XVII or XXVIII 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.
• Compounds of formulae XXIV and XXXI, in which Q represents a single bond and X 2a represents -CHO 5 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
• Thienopyrroles of formulae II, IV, VII 5 X, XIII 5 XV 5 XVII, XXI, XXIII, XXIV, XXV, XXVI, XXVII, XXVIII, XXIX 5 XXXI 5 XXXIII and XXXIV may also be prepared with reference to a standard heterocyclic chemistry textbook (e.g. "Heterocyclic Chemistry" by J. A. Joule, K. Mills and G. F. Smith, 3 rd edition, published by Chapman & Hall or "Comprehensive Heterocyclic Chemistry IF by A. R. Katritzky, C. W. Rees and E. F. V. Scriven, Pergamon Press, 1996) and/or made according to the following general procedures.
• Heterocyclic Chemistry by J. A. Joule, K. Mills and G. F. Smith, 3 rd edition, published by Chapman &
• compounds of formulae II, XXV and XXVI in which X 1 represents H may be prepared by reaction of a compound of formula XXXV,
• SUB represents the substitution pattern that is present in the relevant compound to be formed (i.e. the compound of formula II, XXV or XXVI, respectively), with a compound of formula XXXVI,
• R 4 is as hereinbefore defined and preferably -OR 12a , in which R 12a is as hereinbefore defined and preferably R 12za as hereinbefore defined, under conditions known to the person skilled in the ait (i.e. conditions to induce a condensation reaction, followed by a thermally induced cyclisation).
• the substituents X 1 , R 1 , R 2 , R 3 and R 4 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 4 represents -OR 12a , in which R 12a does not initially represent hydrogen (so providing an ester functional group), the skilled person will appreciate that at any stage during the synthesis (e.g.
• the relevant substituent may be hydrolysed to form a carboxylic acid functional group (in which case R 12a will be hydrogen).
• R 12a will be hydrogen
• the skilled person may also refer to "Comprehensive Organic Functional Group Transformations" by A. R. Katritzky, O. Meth-Cohn and C. W. Rees, Pergamon Press, 1995.
• 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.
• 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.
• AU 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, in which R 4 represents -OR I2a and R 12a 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 S3'nthase-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.
• LTC 4 leukotriene C 4
• FLAP 5-lipoxygenase-activating protein
• 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) 5 bacterial infections, fungal infections, dysmenorrhea, burns, surgical or dental procedures, malignancies (e.g. breast cancer, colon cancer, and prostate cancer),
• viral infections e.g. influenza, common cold, herpes zoster, hepatitis C and AIDS
• malignancies e.g. breast cancer, colon cancer, and prostate cancer
• arthritis • 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 (such as mPGES-1), LTC 4 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 a PGES (and particularly mPGES-1), LTC 4 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 but without proviso (a), to a patient suffering from, or susceptible to, such a condition.
• a member of the MAPEG family such as a PGES (such as mPGES-1), LTC 4 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 a PGES (and particularly mPGES-1), LTC 4 and/or FLAP
• 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 (Le. 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 but without proviso (a), in admixture 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 but without the provisos and in particular proviso (a); 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 (Le. 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 but without the provisos and in particular proviso (a), another therapeutic agent that is useful in the treatment of inflammation, and 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.
• 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/lcg/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
• 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 0 C.
• mPGES- W 2 In the assay mPGES- W 2
• 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. 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 of H 2 O / MeCN (7/3), containing TFA (0.056%), and absorbance is measured at 195 run with a Waters 2487 UV-detector. The following is added chronologically to each well:
• TFA trifluoro acetic acid THF tetrahydrofuran Starting materials and chemical reagents specified in the syntheses described below are commercially available from, e.g. Sigma- Aldrich Fine Chemicals.
• the sub-title compound was prepared in accordance with Example I 5 step (b) from 2-bromo-4-(3-chlorobenzyl)-6-iodothieno [3,2-/3]pyrrole-5-carboxylic acid ethyl ester and 4-terf-butylphenylboronic acid.
• the sub-title compound was prepared in accordance with Preparation 1, step (b) from 2-(5-methylthien-2-yl)thieno[3,2- ⁇ ]pyrrole-5-carboxylic acid ethyl ester (see step (a) above).
• the sub-title compound was prepared in accordance with Example 1 , step (a) from 6-iodo-2-(5-methylthien-2-yl)thieno[3,2- ⁇ ]pyrrole-5-carboxylic acid ethyl ester (see step (b) above) and 3-chlorobenzyl chloride.
• step (d) 4-r3-Chlorobenzyl)-6-iodo-2-(5-methylthien-2-yl)thieno[3,2- ⁇ ]pyrrole-5- carboxylic acid
• step (b) 4-(3-chlorobenzyl)-6-iodo-2-(5-methylthien-2-yl)thieno[3,2-&]pyrrole-5-carbox- ylic acid ethyl ester (see step (c) above).
• Example 9 step (a)) and phenylethynyltrimethylstannane followed by hydrolysis in accordance with ⁇ xample 5, step (c).
• Example 9 step (a)) and (5-methylthiophen-2-yl)trimethyl stannane, followed by hydrolysis in accordance with Example 5 step (c).
• step (b) The title compound was prepared in accordance with Example 10, step (b) from 2-bromo-4-(2-bromobenzyl)thieno[3,2- ⁇ ]pyrrole-5-carboxylic acid ethyl ester (see Example 14, step (a)) and (5-methylthiophen-2-yl)trimethylstannane, followed by hydrolysis in accordance with Example 5, step (c).
• step (b) The title compound was prepared in accordance with Example 10, step (b) from 2-bromo-4-(2-bromobenzyl)thieno[3,2- ⁇ ]pyrrole-5-carboxylic acid ethyl ester (see Example 14, step (a)) and (4-methylthiophen-2-yl)trimethylstannane, followed by hydrolysis accordance with Example 5, step (c).
• Example 9 step (a) and 4-ethoxyphenylboronic acid, followed by hydrolysis in accordance with Example 5, step (c).
• the sub-title compound was prepared in accordance with Example 1, step (a) from 2-bromo-3-methylthieno[3,2- ⁇ ]pyrrole-5-carboxylic acid ethyl ester (see step (b) above) and 3-chlorobenzyl chloride. 6 000188
• Example 5 5 step (b) The title compound was prepared in accordance with Example 5 5 step (b) from 2-bromo-4-(3-chlorobenzyl)-3-methylthieno[3,2- ⁇ ]pyrrole-5-carboxylic acid ethyl ester (see Example 20, step (c)) and phenylethynyltrimethylstannane, followed by hydrolysis in accordance with Example 5, step (c).
• the sub-title compound was prepared in accordance with Preparation I 5 steps (a-c) from 4-bromothiophene-2-carboxaldehyde and azidoacetic acid ethyl ester (step (a)), followed by iodination (step (b)) and TV-alkylation with l-bromornethyl-3,5- bis(trifluoromethyl)benzene (step (c)).
• the sub-title compound was prepared in accordance with Preparation 1, step (V) from NaI (648 mg, 4.32 mmol), iV-chlorosuccinimide (576 mg, 4.32 mmol) and 3-(4-to"f-butylphenyl)thieno[3,2-&]pyriOle-5-carboxylic acid ethyl ester (590 mg, 1.80 mmol). Yield 829 mg (80%).
• Example 26 The title compound was prepared in accordance with Example 26 from 2-(4-iso- propoxyphenyl)thieno[3,2- ⁇ ]pyrrole-5-carboxylic acid ethyl ester (see Example 26, step (a)) and 5-bromo-2-isopropoxypyridine, followed by hydrolysis.
• Example 26 The title compound was prepared in accordance with Example 26 from 2-(4-iso- propoxyphenyl)thieno[3,2- ⁇ ]pyrrole-5-carboxylic acid ethyl ester (see Example 26, step (a)) and 3-(4-bromophenyl)acrylic acid ethyl ester, followed by hydrolysis.
• step (a)) and 5-bromo-5'-methyl-[2,2']bithiophenyl see step (a) above, followed by hydrolysis.
• the title compound was prepared in accordance with Example 33 from 2-bromo- thieno[3,2- ⁇ ]pyrrole-5-carboxylic acid ethyl ester (see Preparation 1 (a)), 4-isopropoxyphenylboronic acid and (5-methylthien-2-yl)tributylstannane, followed by hydrolysis.
• the sub-title compound was prepared in accordance with Example 5, step (b) from 2-bromo-6-(3-chlorobenzyl)thieno[2,3- ⁇ ]pyrrole-5-carboxylic acid ethyl ester (see step (c) above) and (4-isopropoxyphenyl)trimethylstannane.
• 6-r3-Chlorobenzyl)-2-(5-methylthien-2-yl)thieno[2,3-6]pyrrole-5-carboxylic acid The title compound was prepared in accordance with Example 35 from 2-bromo- 6-(3-chlorobenzyl)thieno[2,3- ⁇ ]p3'rrole-5-carboxylic acid ethyl ester (see Example 35, step (c)) and (5-methylthiophen-2-yl)tributylstannane, followed by hydrolysis.
• 6-f3-CMorobenzyl)-2-f4-methylthien-2-yl ' )thieno[2,3-&]pyrrole-5-carboxylic acid The title compound was prepared in accordance with Example 35 from 2-bromo- 6-(3-chlorobenzyl)thieno[2,3-b]pyrrole-5-carboxylic acid ethyl ester (see Example 35, step (c)) and (4-methylthiophen-2-yl)tributylstannane, followed by hydrolysis.
• Example 2 • 390 nM
• Example 4 1300 nM

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