Patent Application
20090069384
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. Members of the MAPEG family include the microsomal prostaglandin E synthase-1 (mPGES-1), 5-lipoxygenase-activating protein (FLAP), leukotriene C4 synthase and microsomal glutathione S-transferases (MGST1, 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.
There are many diseases/disorders that are inflammatory in their nature. One of the major problems associated with existing treatments of inflammatory conditions is a lack of efficacy and/or the prevalence of side effects (real or perceived).
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 β-agonists which affect the bronchoconstriction element, whereas patients with more severe asthma typically are treated regularly with inhaled corticosteroids which to a large extent are anti-inflammatory in their nature.
Another common disease of the airways with inflammatory and bronchoconstrictive components is chronic obstructive pulmonary disease (COPD). The disease is potentially lethal, and the morbidity and mortality from the condition is considerable. At present, there is no known pharmacological treatment capable of changing the course of the disease.
The cyclooxygenase (COX) enzyme exists in two forms, one that is constitutively expressed in many cells and tissues (COX-1), and one that is induced by pro-inflammatory stimuli, such as cytokines, during an inflammatory response (COX-2).
COXs metabolise arachidonic acid to the unstable intermediate prostaglandin H2 (PGH2). PGH2 is further metabolized to other prostaglandins including PGE2, PGF2α, PGD2, prostacyclin and thromboxane A2. These arachidonic acid metabolites are known to have pronounced physiological and pathophysiological activity including pro-inflammatory effects.
PGE2 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 PGE2, including “NSAIDs” (non-steroidal antiinflammatory drugs) and “coxibs” (selective COX-2 inhibitors). These drugs act predominantly by inhibition of COX-1 and/or COX-2, thereby reducing the formation of PGE2.
However, 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. For example, 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.
An alternative treatment of inflammatory diseases that does not give rise to the above-mentioned side effects would thus be of real benefit in the clinic. In particular, a drug that inhibits (preferably selectively) the transformation of PGH2 to the pro-inflammatory mediator PGE2 might be expected to reduce the inflammatory response in the absence of a corresponding reduction of the formation of other, beneficial arachidonic acid metabolites. Such inhibition would accordingly be expected to alleviate the undesirable side-effects mentioned above.
PGH2 may be transformed to PGE2 by prostaglandin E synthases (PGES). Two microsomal prostaglandin E synthases (mPGES-1 and mPGES-2), and one cytosolic prostaglandin E synthase (cPGES) have been described.
The leukotrienes (LTs) 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 C4, D4 and E4 (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 CysLT1 and CysLT2. As an alternative to steroids, leukotriene receptor antagonists (LTRas) have been developed in the treatment of asthma. These drugs may be given orally, but do not control inflammation satisfactorily. The presently used LTRas are highly selective for CysLT1. 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 C4 synthase may be mentioned. A FLAP inhibitor would also decrease the formation of the proinflammatory LTB4.
mPGES-1, FLAP and leukotriene C4 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 (MGST1, MGST2 and MGST3). For a review, c.f. P.-J. Jacobsson et al in Am. J. Respir. Crit. Care Med. 161, S20 (2000). It is well known that 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. Claveau et al in J. Immunol. 170, 4738 (2003). The former paper also describes that such compounds may also display notable cross-reactivity with proteins in the arachidonic acid cascade that do not belong to the MAPEG family, e.g. 5-lipoxygenase.
Thus, agents that are capable of inhibiting the action of mPGES-1, and thus reducing the formation of the specific arachidonic acid metabolite PGE2, 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 thienopyrrol-5-yl-(4-methylpiperazinyl-1-yl)methanone derivatives for use in the treatment of diseases mediated by the histamine H4 receptor. However, this document does not disclose compounds with aromatic substituents attached to the ring system via the pyrrole nitrogen.
Certain thieno[2,3-b]pyrrol-5-yl carboxylic esters have been disclosed by Sommen et al in Tetrahedron, 59, 1557 (2003) and Synlett, 1731 (2001), by El-Hamed et al in Bulletin of the Faculty of Pharmacy (Cairo University), 39, 11 (2001), and by El-Shafei et al in Phosphorus, Sulfur and Silicon and the Related Elements, 73, 15 (2001), as chemical curiosities. The use of these compounds in the treatment of inflammation is neither mentioned nor suggested in any of these documents.
Kumar et al recently disclosed certain thieno[3,2-b]pyrrol-5-yl carboxylic esters as antiinflammatory agents in Bioorg. Med. Chem., 12, 1221 (2004). However, compounds that are substituted with an aryl group, or a heteroaryl group, attached either directly or via a linker at the 4(N)-position and/or substituted with either an aryl group, a heteroaryl group or heterocycloalkyl group at the 2-position, i.e. on the thiophene ring are neither mentioned nor suggested in these documents.
Finally, international patent application WO 99/40914 discloses 4(N)-benzylthienopyrrol-5-yl carboxylic acids and esters for use as inhibitors of monocyte chemoattractant protein-1 (MCP-1).
According to the invention there is provided a compound of formula I,
wherein
one of U and V represents —S— and the other represents —C(R3)—;
when U represents —S—, the dotted line between the carbon atom bearing R2 and V is a double bond and that between the carbon atom bearing R2 and U is a single bond, and when V represents —S—, the dotted line between the carbon atom bearing R2 and U is a double bond and that between the carbon atom bearing R2 and V is a single bond;
one of the groups R2 and R3 represents -D-E and the other represents H, halo, —NO2, cyano or C1-6 alkyl, which alkyl group is optionally substituted by one or more substituents selected from halo, hydroxy and C1-6 alkoxy;
D represents a single bond, —O—, —C(R6)(R7)—, C2-4 alkylene, —C(O)— or —S(O)m—;
R1 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 G1 and/or Z1);
R6 and R7 independently represent H, halo or C1-6 alkyl, which latter group is optionally substituted by halo, or R6 and R7 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 C1-3 alkyl, which latter group is optionally substituted by one or more halo substituents;
X1 represents H, halo, —N(R8)-J-R9 or -Q-X2;
J represents a single bond, —C(O)— or —S(O)m—;
Q represents a single bond, —O—, —C(O)— or —S(O)m—;
m represents, on each occasion when mentioned above, 0, 1 or 2;
X2 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) C1-8 alkyl or a heterocycloalkyl group, both of which are optionally substituted by one or more substituents selected from G1 and/or Z1;
Y represents a single bond, or a C1-8 alkylene or C2-8 heteroalkylene chain, both of which latter two groups:
(i) optionally contain one or more unsaturations (for example double or triple bonds);
(ii) are optionally substituted by one or more substituents selected from halo, —R10a, —N(R10b)R11b, —OR10c and ═O; and/or
(iii) may comprise an additional 3- to 8-membered ring formed between any one or more (e.g. one or two) members of the C1-8 alkylene or C2-8 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 halo, —R10d, —N(R10e)R11e, —OR10f and ═O;
R4 represents —OR12a or —N(R12b)R13b;
R8, R9, R10a to R10f, R11b, R11e, R12a, R12b and R13b independently represent, on each occasion when mentioned above:
I) hydrogen;
II) an aryl group or a heteroaryl group, both of which are optionally substituted by one or more substituents selected from B;
III) C1-8 alkyl or a heterocycloalkyl group, both of which are optionally substituted by one or more substituents selected from G1 and/or Z1; or
R8 and R9, R10b and R11b, R10e and R11e, and R12b and R13b (as appropriate), may be linked together to form, along with the N atom and (in the case of R9) 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 G1 and/or Z1;
A represents, on each occasion when mentioned above:
I) an aryl group or a heteroaryl group, both of which are optionally substituted by one or more substituents selected from B;
II) C1-8 alkyl or a heterocycloalkyl group, both of which are optionally substituted by one or more substituents selected from G1 and/or Z1; or
III) a G1 group;
G1 represents, on each occasion when mentioned above, halo, cyano, —N3, —NO2, —ONO2 or -A1-R14a;
wherein A1 represents a single bond or a spacer group selected from —C(O)A2-, —S(O)2A3-, —N(R15a)A4- or —OA5-, in which:
A2 represents a single bond, —O—, —N(R15b)— or —C(O)—;
A3 represents a single bond, —O— or —N(R15c)—;
A4 and A5 independently represent a single bond, —C(O)—, —C(O)N(R15d)—, —C(O)O—, —S(O)2— or —S(O)2N(R15e)—;
Z1 represents, on each occasion when mentioned above, ═O, ═S, ═NOR14b, ═NS(O)2N(R15f)R14c, ═NCN or ═C(H)NO2;
B represents, on each occasion when mentioned above:
I) an aryl group or a heteroaryl group, both of which are optionally substituted by one or more substituents selected from G2;
II) C1-8 alkyl or a heterocycloalkyl group, both of which are optionally substituted by one or more substituents selected from G2 and/or Z2; or
III) a G2 group;
G represents, on each occasion when mentioned above, halo, cyano, —N3, —NO2, —ONO2 or -A6-R16a;
wherein A6 represents a single bond or a spacer group selected from —C(O)A7-, —S(O)2A8-, —N(R17a)A9- or —OA10-, in which:
A7 represents a single bond, —O—, —N(R17b)— or —C(O)—;
A8 represents a single bond, —O— or —N(R17c)—;
A9 and A10 independently represent a single bond, —C(O)—, —C(O)N(R17d)—, —C(O)O—, —S(O)2— or —S(O)2N(R17e)—;
Z2 represents, on each occasion when mentioned above, ═O, ═S, ═NOR16b, ═NS(O)2N(R17f)R16c, ═NCN or —C(H)NO2;
R14a, R14b, R14c, R15a, R15b, R15c, R15d, R15e, R15f, R16a, R16b, R16c, R17a, R17b, R17c, R17d, R17e and R17f 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 G3;
iii) C1-8 alkyl or a heterocycloalkyl group, both of which are optionally substituted by one or more substituents selected from G3 and/or Z3; or
any pair of R14a to R14c and R15a to R15f, and/or R16a to R16c and R17a to R17f, 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 G3 and/or Z3;
G3 represents, on each occasion when mentioned above, halo, cyano, —N3, —NO2, —ONO2 or -A11-R18a;
wherein A11 represents a single bond or a spacer group selected from —C(O)A12-, —S(O)2A13-, —N(R19a)A14- or —OA15-, in which:
A12 represents a single bond, —O—, —N(R19b)— or —C(O)—;
A13 represents a single bond, —O— or —N(R19c)—;
A14 and A15 independently represent a single bond, —C(O)—, —C(O)N(R19d)—, —C(O)O—, —S(O)2— or —S(O)2N(R19e)—;
Z3 represents, on each occasion when mentioned above, ═O, ═S, ═NOR18b, ═NS(O)2N(R19f)R18c, ═NCN or ═C(H)NO2;
R18a, R18b, R18c, R19a, R19b, R19c, R19d, R19e and R19f are independently selected from:
i) hydrogen;
ii) C1-6 alkyl or a heterocycloalkyl group, both of which groups are optionally substituted by one or more substituents selected from halo, C1-4 alkyl, —N(R20a)R21a, —OR20b and ═O; and
iii) an aryl or heteroaryl group, both of which are optionally substituted by one or more substituents selected from halo, C1-4 alkyl, —N(R20c)R21b and —OR20d; or any pair of R18a to R18c and R19a to R19f 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, CM alkyl, —N(R20e)R21c, —OR20f and ═O;
R20a, R20b, R20c, R20d, R20e, R20f, R21a, R21b and R21c are independently selected from hydrogen and C1-4 alkyl, which latter group is optionally substituted by one or more halo groups;
or a pharmaceutically-acceptable salt thereof,
provided that, when R2 represents -D-E and:
(a) V represents S, D represents —C(O)—, E represents phenyl, X1 represents -Q-X2, Q represents a single bond, R3 and X2 both represent methyl, R4 represents ethoxy and Y represents a single bond, then R1 does not represent an unsubstituted phenyl group; and
(b) when U represents S, D represents a single bond, E represents thien-2-yl or 3-aminophenyl, X1 and R3 both represent H, R4 represents —OH or ethoxy and Y represents —CH2—, then R1 does not represent 3,4-dichlorophenyl,
which compounds and salts are referred to hereinafter as “the compounds of the invention”.
Pharmaceutically-acceptable 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 (entgegen) 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. All 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, techniques. Alternatively 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.
Unless otherwise specified, C1-q alkyl, the alkyl part of C1-q alkoxy, and C1-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 C3-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 minimum of two) of carbon atoms, be unsaturated (forming, for example, in the case of alkyl, a C2-q alkenyl or a C2-q alkynyl group or, in the case of alkylene, a C2-q alkenylene or a C2-q alkynylene group).
C3-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 C3-q cycloalkenyl or a C8-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.
C2-8 heteroalkylene chains include C2-8 alkylene chains that are interrupted by one or more heteroatom groups selected from —O—, —S— or —N(R24)—, in which R24 represents C1-4 alkyl, optionally substituted by one or more halo (e.g. fluoro) groups.
The term “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 C2-q heterocycloalkenyl (where q is the upper limit of the range) or a C8-q heterocycloalkynyl group. C2-q heterocycloalkyl groups that may be mentioned include 7-azabicyclo[2.2.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl, 6-azabicyclo[3.2.1]-octanyl, 8-azabicyclo-[3.2.1]octanyl, aziridinyl, azetidinyl, dihydropyranyl, dihydropyridyl, dihydropyrrolyl (including 2,5-dihydropyrrolyl), dioxolanyl (including 1,3-dioxolanyl), dioxanyl (including 1,3-dioxanyl and 1,4-dioxanyl), dithianyl (including 1,4-dithianyl), dithiolanyl (including 1,3-dithiolanyl), imidazolidinyl, imidazolinyl, morpholinyl, 7-oxabicyclo[2.2.1]heptanyl, 6-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-tetrahydropyridyl), thietanyl, thiiranyl, thiolanyl, thiomorpholinyl, trithianyl (including 1,3,5-trithianyl), tropanyl and the like. Substituents on heterocycloalkyl groups may, where appropriate, be located on any atom in the ring system including a heteroatom. Further, in the case where the 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. The point of attachment of heterocycloalkyl groups may be via any atom in the ring system including (where appropriate) a heteroatom (such as a nitrogen atom), or an atom on any fused carbocyclic ring that may be present as part of the ring system. Heterocycloalkyl groups may also be in the N- or S-oxidised form.
For the avoidance of doubt, the term “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. The term “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 C6-14 (such as C6-13 (e.g. C6-10)) 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. C6-14 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. 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 3,4-dihydro-2H-1,4-benzoxazinyl), benzoxazolyl, benzomorpholinyl, benzoselenadiazolyl (including 2,1,3-benzoselenadiazolyl), benzothienyl, carbazolyl, chromanyl, cinnolinyl, furanyl, imidazolyl, imidazo[1,2-a]pyridyl, indazolyl, indolinyl, indolyl, isobenzofuranyl, isochromanyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiaziolyl, isoxazolyl, naphthyridinyl (including 1,6-naphthyridinyl or, preferably, 1,5-naphthyridinyl and 1,8-naphthyridinyl), oxadiazolyl (including 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl and 1,3,4-oxadiazolyl), oxazolyl, phenazinyl, phenothiazinyl, phthalazinyl, pteridinyl, purinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinolizinyl, quinoxalinyl, tetrahydroisoquinolinyl (including 1,2,3,4-tetrahydroisoquinolinyl and 5,6,7,8-tetrahydroisoquinolinyl), tetrahydroquinolinyl (including 1,2,3,4-tetrahydroquinolinyl and 5,6,7,8-tetrahydroquinolinyl), tetrazolyl, thiadiazolyl (including 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl and 1,3,4-thiadiazolyl), thiazolyl, thiochromanyl, thienyl, triazolyl (including 1,2,3-triazolyl, 1,2,4-triazolyl and 1,3,4-triazolyl) and the like. Substituents on 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 N- or S-oxidised form.
Heteroatoms that may be mentioned include phosphorus, silicon, boron, tellurium, selenium and, preferably, oxygen, nitrogen and sulphur.
For the avoidance of doubt, in cases in which 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. For example, in the situation in which R1 and X2 are both aryl groups substituted by one or more C1-8 alkyl groups, the alkyl groups in question may be the same or different. Similarly, when 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. For example, when X2 and/or R1 represents e.g. an aryl group substituted by G1 in addition to, for example, C1-8 alkyl, which latter group is substituted by G1, the identities of the two G1 groups are not to be regarded as being interdependent.
For the avoidance of doubt, when a term such as “R10a to R10c” is employed herein, this will be understood by the skilled person to mean R10a, R10b and R10c inclusively.
Compounds of the invention that may be mentioned include those in which when E represents an optionally substituted heterocycloalkyl group, it is a C4-5 heterocycloalkyl 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 G1 and/or, preferably, Z1.
Further compounds of the invention that may be mentioned include those in which when E represents an optionally substituted heterocycloalkyl group, then D represents C1-3 alkylene or, preferably, a single bond.
Yet 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 G1; an aryl group or a heteroaryl group, both of which are optionally substituted by one or more B groups; a C1-5 alkyl group, which alkyl group is optionally unsaturated and is optionally substituted by one or more G1 groups;
X2 represents optionally substituted aryl or heteroaryl, C1-6 alkyl or heterocycloalkyl (which latter two groups are preferably substituted with one or more (e.g. one) groups selected from G1 and/or Z1);
R8 represents H or C1-2 alkyl (e.g. methyl);
R9 represents C1-6 (e.g. C1-3) alkyl, which group may be unsubstituted, but is preferably substituted by one or more (e.g. one) groups selected from G1;
or R8 and R9 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 R8 and R9 are respectively attached) a further heteroatom (e.g. nitrogen or oxygen) and which ring is optionally substituted by one or more (e.g. two) Z1 groups;
R10a to R10f, R11b and R11e independently represent H or C1-2 alkyl;
G1 represents halo, —NO2 or -A1-R14a;
A1 represents —N(R15a)A4- or, preferably, a single bond, —C(O)A2- or —OA5-;
A2 represents —O—;
A4 and A5 independently represent a single bond, —C(O)—, —C(O)N(R15d)— or —C(O)O—;
R14a to R14c independently represent hydrogen, an aryl group, a heteroaryl group, C1-7 alkyl or a heterocycloalkyl group (such as C4-8 heterocycloalkyl, which group contains one nitrogen atom and, optionally, a further nitrogen or oxygen atom), which latter four groups are optionally substituted by one or more G3 groups and/or (in the case of alkyl and heterocycloalkyl) Z3 groups;
R15a to R15f independently represent C1-2 alkyl or, preferably, hydrogen;
or any pair of R14a to R14c and R15a to R15f, together with the atom(s) to which they are attached, represent a nitrogen-containing heterocycloalkyl group optionally substituted by one or more G3 and/or Z3 groups;
Z1 represents ═NOR14b, ═NCN or, preferably, ═O;
B represents C1-3 alkyl or G2;
G2 represents cyano, —N3, halo, —NO2 or -A6-R16a;
A6 represents —N(R17a)A9- or —OA10-;
A9 represents —C(O)N(R17d)—, —C(O)O— or, more preferably, a single bond or —C(O)—;
A10 represents a single bond;
R16a to R16c independently represent C1-3 alkyl;
Z2 represents ═NOR16b, ═NCN or, more preferably, ═O;
G3 represents halo or -A11-R18a;
A11 represents a single bond, —OA15- or, more preferably, —C(O)A12-;
A12 represents —O—;
A15 represents a single bond,
when any one of R18a, R18b, R18c, R19a, R19b, R19c, R19d, R19e and R19f represents optionally substituted C1-6 alkyl, the optional substituent is one or more halo groups;
R18a to R18c independently represent C1-4 alkyl, aryl or H;
Z3 represents ═O;
J represents a single bond, —C(O)— or —S(O)2—;
when any one of R20a, R20b, R20c, R20d, R20e, R20f, R21a, R21b and R21c represents optionally substituted C1-4 alkyl, the optional substituent is one or more fluoro groups.
Preferred aryl and heteroaryl groups that R1, X2 (when X2 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-imidazolyl), oxazolyl, isoxazolyl, thiazolyl, pyridyl (e.g. 2-pyridyl, 3-pyridyl or 4-pyridyl), indazolyl, indolyl, indolinyl, isoindolinyl, quinolinyl, 1,2,3,4-tetrahydroquinolinyl, isoquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, quinolinyl, benzo furanyl, isobenzofuranyl, chromanyl, benzothienyl, pyridazinyl, pyrimidinyl, pyrazinyl, indazolyl, benzimidazolyl, quinazolinyl, quinoxalinyl, 1,3-benzodioxolyl, tetrazolyl, benzo thiazolyl, and/or benzo dioxanyl, group. Preferred values include phenyl, thienyl, pyridyl and imidazolyl.
Preferred values of E, when R2 and/or R3 represent -D-E include optionally substituted pyridyl, phenyl, thienyl (e.g. 2-thienyl) and imidazolyl.
Preferred values of R1 include optionally substituted phenyl, thienyl (e.g. 2-thienyl), pyridyl (e.g. 2-pyridyl and 3-pyridyl) and imidazolyl.
More preferred compounds of the invention include those in which:
X1 represents H, halo (such as iodo, chloro or fluoro) or -Q-X2;
Q represents —O—, —S— or, more preferably, a single bond;
X2 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 C1-3 alkyl (e.g. methyl or ethynyl) group optionally substituted with one or more G1 groups;
A represents G1; 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 t-butyl group, each of which is optionally substituted by one or more G1 groups;
Y represents a C1-3 alkylene spacer group (such as an ethylene or, preferably, a methylene group) or, more preferably, a single bond;
the R2 or R3 group (as appropriate) that does not represent -D-E represents H, halo (such as iodo) or C1-3 alkyl (such as methyl);
D represents —C(R6)(R7)— or, preferably, a single bond or a C1-3 alkylene (e.g. an ethynylene) linker group;
R6 and R7 independently represent H, fluoro or C1-6 (e.g. C1-2) alkyl (such as methyl); or
R6 and R7 are linked together to form a C3-6 (e.g. C3-4) cycloalkyl group;
R12a and R12b independently represent H or C1-3 alkyl, such as methyl;
when R4 represents —N(R12b)R13b, R12b represents H and R13b represents a C1-4 alkyl group (e.g. an ethyl group) substituted by G1;
when R4 represents —OR12a, R12a represents H;
G1 represents fluoro, chloro, —NO2 or -A1-R14a;
A4 and A5 independently represent a single bond;
R14a to R14c 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, 4-pyridyl) or thiazolyl (e.g. 5-thiazolyl)) group, a linear C1-6 alkyl group (such as a methyl or an ethyl group), an unsaturated C2-6 alkyl group (such as an ethenyl or an ethynyl group), a branched C2-6 alkyl group (such as an isopropyl group), or a cyclic C3-6 alkyl group (such as a cyclopropyl or cyclopentyl group), which latter six groups are optionally substituted with one or more G3 substituents;
B represents methyl or G2;
G2 represents -A6-R16a;
A6 represents —OA10-;
R16a to R16c independently represent methyl or ethyl;
G3 represents fluoro or -A11-R18a;
A11 represents —C(O)O—;
R18a to R18c independently represent C1-3 alkyl (such as a methyl group or an ethyl group), a phenyl group or, more preferably, H.
Optional substituents on R1, X2 (when X2 represents an aryl or heteroaryl group) and E groups are preferably selected from:
halo (e.g. fluoro, chloro or bromo);
cyano;
C1-6 alkyl, which alkyl group may be linear or branched (e.g. C1-4 alkyl (including ethyl, n-propyl, isopropyl, n-butyl or, preferably, methyl or r-butyl), n-pentyl, isopentyl, n-hexyl or isohexyl), cyclic (e.g. cyclopropyl, cyclobutyl, cyclohexyl or, preferably, cyclopentyl), part-cyclic (e.g. cyclopropylmethyl), unsaturated (e.g. 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 4-pentenyl, 5-hexenyl or, preferably, ethenyl, or ethynyl) and/or optionally substituted with one or more —CO2H groups (so forming e.g. a carboxyvinyl group), one or more halo (e.g. fluoro) group (so forming e.g. a fluoromethyl, a difluoromethyl or, preferably, a trifluoromethyl group), or one or more phenyl groups (so forming e.g. a phenylethynyl group);
aryl (e.g. phenyl), optionally substituted by one or more halo or, preferably, C1-4 alkoxy (e.g. ethoxy or isopropoxy) group;
heteroaryl (e.g. thienyl, such as thien-2-yl), optionally substituted by one or more halo or, preferably, C1-3 alkyl (e.g. methyl) group;
heterocycloalkyl, such as a C4-5 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 C1-3 alkyl (e.g. methyl) and ═O;
wherein R22 and R23 independently represent, on each occasion when mentioned above, H, phenyl or C1-6 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl or cyclopropyl (which alkyl groups are optionally substituted by one or more —CO2H 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)).
Particularly preferred values of X2 include C1-3 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.
Particularly preferred compounds of the invention include those of the examples described hereinafter.
Compounds of the invention may be made in accordance with techniques that are well known to those skilled in the art, for example as described hereinafter.
According to a further aspect of the invention there is provided a process for the preparation of a compound of formula I, which process comprises:
(i) reaction of a compound of formula II,
wherein the dotted lines, U, V, X1, R2 and R4 are as hereinbefore defined, with a compound of formula III,
R1YL1 III
wherein L1 represents a suitable leaving group such as chloro, bromo, iodo, a sulfonate group (e.g. —OS(O)2CF3, —OS(O)2CH3, —OS(O)2PhMe or a nonaflate) or —B(OH)2 and R1 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 CuI/diamine complex), Pd(OAc)2, Pd2(dba)3 or NiCl2 and an optional additive such as PPh3, 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, xantphos, NaI or an appropriate crown ether, such as 18-crown-6-benzene, in the presence of an appropriate base such as NaH, Et3N, pyridine, N,N′-dimethylethylenediamine, Na2CO3, K2CO3, K3PO4, Cs2CO3, t-BuONa or t-BuOK (or a mixture thereof), in a suitable solvent (e.g. dichloromethane, dioxane, toluene, ethanol, isopropanol, dimethylformamide, ethylene glycol, ethylene glycol dimethyl ether, water, dimethylsulfoxide, acetonitrile, dimethylacetamide, N-methylpyrrolidinone, tetrahydrofuran or a mixture thereof) or in the absence of an additional solvent when the reagent may itself act as a solvent (e.g. when R1 represents phenyl and L1 represents bromo, i.e. bromobenzene). Tins 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;
(ii) for compounds of formula I in which X1 represents -Q-X2, in which Q is a single bond or —C(O)—, reaction of a compound of formula IV,
wherein the dotted lines, U, V, L1, R1, R2, R4 and Y are as hereinbefore defined, with a compound of formula V,
X2-Qa-L2 V
wherein Qa represents a single bond or —C(O)—, L2 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-1,3,2-dioxaborolan-2-yl group, 9-borabicyclo[3.3.1]nonane (9-BBN), —Sn(alkyl)3 (e.g. —SnMe3 or —SnBu3), or a similar group known to the skilled person, and X2 is as hereinbefore defined. The skilled person will appreciate that L1 and L2 will be mutually compatible. In this respect, preferred leaving groups for compounds of formula V in which Qa is —C(O)— include chloro or bromo groups, and preferred leaving groups for compounds of formula V in which Qa is a single bond include —B(OH)2, 4,4,5,5-tetramethyl-1,3,2-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 (or a salt or complex thereof) such as CuI, Pd/C, PdCl2, Pd(OAc)2, Pd(PPh3)2Cl2, Pd(PPh3)4, Pd2(dba)3 or NiCl2 and a ligand such as t-Bu3P, (C6H11)3P, PPh3, AsPh3, P(o-Tol)3, 1,2-bis(diphenylphosphino)-ethane, 2,2′-bis(di-tert-butylphosphino)-1,1′-biphenyl, 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, 1,1′-bis(diphenyl-phosphinoferrocene), 1,3-bis(diphenylphosphino)propane, xantphos, or a mixture thereof, together with a suitable base such as, Na2CO3, K3PO4, Cs2CO3, NaOH, KOH, K2CO3, CsF, Et3N, (i-Pr)2NEt, t-BuONa or t-BuOK (or mixtures thereof) in a suitable solvent such as dioxane, toluene, ethanol, dimethylformamide, ethylene glycol dimethyl ether, water, dimethylsulfoxide, acetonitrile, dimethylacetamide, N-methylpyrrolidinone, tetrahydrofuran or mixtures thereof. The 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. The skilled person will appreciate that certain compounds of formula IV (in particular those in which L1 represents chloro, bromo or iodo) are also compounds of formula I and therefore compounds of the invention. In the case where Qa represents a single bond and X2 represents either C2-8 alkenyl, cycloalkenyl or heterocycloalkenyl in which the double bond is between the carbon atoms that are α and β to L2, the skilled person will appreciate that the double bond may migrate on formation of the compound of formula I to form a double bond that is between the carbon atoms that are β and γ to the indole ring;
(iii) for compounds of formula I in which X1 represents -Q-X2 and Q represents —C(O)—, reaction of a compound of formula I in which X1 represents H with a compound of formula V in which Qa represents —C(O)— and L2 represents a suitable leaving group such as chloro or bromo, —N(C1-6 alkyl)2 (e.g. —N(CH3)2) or a carboxylate group such as —O—C(O)—X2y in which X2y represents X2 or H. In the latter case, X2y and X2 are preferably the same, or X2y represents e.g. H, CH3 or CF3. 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. AlCl3 or FeCl3). Reaction of a compound of formula V in which L2 represents —N(C1-6 alkyl)2 and X2 represents optionally substituted aryl (e.g. phenyl) or heteroaryl may be performed in the presence of a reagent such as POCl3, for example under reaction conditions described in Bioorg. Med. Chem. Lett., 14, 4741-4745 (2004). The skilled person will appreciate that in the latter instance, POCl3 may convert the compound of formula V into one in which L2 represents chloro and/or Qa 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 X1 represents H;
(iv) for compounds of formula I in which X1 represents —N(R8)-J-R9 or -Q-X2 in which Q represents —O— or —S—, reaction of a compound of formula IV as hereinbefore defined with a compound of formula VI,
X1bH VI
in which X1b represents —N(R8)-J-R9 or -Q-X2 in which Q represents —O— or —S— and R8, J, R9 and X2 are as hereinbefore defined, for example under reaction conditions as hereinbefore described in respect of either process (i) or (ii) above;
(v) for compounds of formula I in which X1 represents -Q-X2 and Q represents —S—, reaction of a compound of formula I in which X1 represents H, with a compound of formula VI in which X1b represents -Q-X2, Q represents —S— and X2 is as hereinbefore defined, for example in the presence of N-chlorosuccinimide and a suitable solvent (e.g. dichloromethane), e.g. as described in inter alia Org. Lett., 819-821 (2004). Alternatively, reaction of a compound of formula VI in which X1b represents -Q-X2, Q represents —S— and X2 represents an optionally substituted aryl (phenyl) or heteroaryl (e.g. 2-pyridyl) group, may be performed in the presence of PIFA (PhI(OC(O)CF3)2) in a suitable solvent such as (CF3)2CHOH. Introduction of such an —S—X2 group is described in inter alia Bioorg. Med. Chem. Lett., 14, 4741-4745 (2004);
(vi) for compounds of formula I in which X1 represents -Q-X2 and Q represents —S(O)— or —S(O)2—, oxidation of a corresponding compound of formula I in which Q represents —S— under appropriate oxidation conditions, which will be known to those skilled in the art;
(vii) for compounds of formula I in which X1 represents -Q-X2, X2 represents C1-8 alkyl substituted by G1, G1 represents -A1-R14a, A1 represents —N(R15a)A4- and A4 is a single bond (provided that Q represents a single bond when X2 represents substituted C1 alkyl), reaction of a compound of formula VII,
wherein X2a represents a C1-8 alkyl group substituted by a Z1 group in which Z1 represents ═O, Q is as hereinbefore defined, provided that it represents a single bond when X2a represents C1 alkyl substituted by ═O (i.e. —CHO), and the dotted lines, U, V, R1, R2, R4 and Y are as hereinbefore defined under reductive amination conditions in the presence of a compound of formula VIII,
R14a(R15a)NH VIII
wherein R14a and R15a are as hereinbefore defined, under conditions well known to those skilled in the art;
(viia) for compounds of formula I in which X1 represents -Q-X2, Q represents a single bond, X2 represents methyl substituted by G1, G1 represents -A1-R14a, A1 represents —N(R15a)A4-, A4 is a single bond and R14a and R15a are preferably methyl, reaction of a corresponding compound of formula I in which X1 represents H, with a mixture of formaldehyde (or equivalent reagent) and a compound of formula VIII as hereinbefore defined (e.g. in which R14a and R15a represent methyl), for example in the presence of solvent such as a mixture of acetic acid and water, under e.g. standard Mannich reaction conditions known to those skilled in the art;
(viii) for compounds of formula I in which X1 represents -Q-X2, Q represents a single bond and X2 represents optionally substituted C2-8 alkenyl (in which a point of unsaturation is between the carbon atoms that are α and β to the indole ring and the optional substituents are preferably other than G1 in which G1 represents -A1-R14a, A1 represents —OA5- or —N(R15a)A4-, A4 and A5 both represent a single bond and R14a represents hydrogen), reaction of a corresponding compound of formula IV in which L1 represents halo (e.g. iodo) with a compound of formula IXA,
H2C═C(H)X2b IXA
or, depending upon the geometry of the double bond, reaction of a compound of formula VII in which Q represents a single bond and X2a represents —CHO with either a compound of formula IXB,
(EtO)2P(O)CH2X2b IXB
or the like, or a compound of formula IXC,
(Ph)3P═CHX2b IXC
or the like, wherein, in each case, X2b represents H, G1 (wherein G1 is preferably other than -A1-R14a in which A1 represents —OA5- or —N(R15a)A4-, A4 and A5 both represent a single bond and R14a represents hydrogen) or C1-6 alkyl optionally substituted with one of more substituents selected from G1 and/or Z1 and G1 and Z1 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 PdCl2(PPh3)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 IXB, or IXC, under standard Horner-Wadsworth-Emmons, or Wittig, reaction conditions, respectively;
(ix) for compounds of formula I in which X1 represents -Q-X2 and X2 represents optionally substituted, saturated C2-8 alkyl, saturated cycloalkyl, saturated heterocycloalkyl, C2-8 alkenyl, cycloalkenyl or hetero cycloalkenyl, reduction (e.g. hydrogenation) of a corresponding compound of formula I in which X2 represents optionally substituted C2-8 alkenyl, cycloalkenyl, heterocycloalkenyl, C2-8 alkynyl, cycloalkynyl or heterocycloalkynyl (as appropriate) under conditions that are known to those skilled in the art. For example, in the case where an alkynyl group is converted to an alkenyl group, in the presence of an appropriate poisoned catalyst (e.g. Lindlar's catalyst);
(x) for compounds of formula I in which D represents a single bond, —C(O)—, —C(R6)(R7)—, C2-4 alkylene or —S(O)2—, reaction of a compound of formula X,
wherein L3 represents L1 or L2 as hereinbefore defined, which group is attached to one or both of the two carbon atoms of the thienoid ring of the thienopyrrole, R2-R3 represents whichever other substituent on the thienoid ring, i.e. R2 or R3, is already present in that ring, and the dotted lines, U, V, X1, R1, R2, R3, R4 and Y are as hereinbefore defined, with a compound of formula XI,
E-Da-L4 XI
wherein Da represents a single bond, —C(O)—, —C(R6)(R7)—, C2-4 alkylene or —S(O)2—, L4 represents L1 (when L3 is L2) or L2 (when L3 is L1) and L1, L2, E, R6 and R7 are as hereinbefore defined. For example, when Da represents a single bond, —C(O)— or C2-4 alkylene, the reaction may be performed for example under similar conditions to those described hereinbefore in respect of process step (ii) above. Further, when Da represents —C(O)—, —C(R6)(R7)—, C2-4 alkylene or —S(O)2—, the reaction may be performed by first activating the compound of formula X.
The skilled person will appreciate that compounds of formula X may be activated when L3 represents halo, by:
The skilled person will also appreciate that the 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 ZnCl2) 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;
(xi) for compounds of formula I in which D represents —S—, —O— or C2-4 alkynylene in which the triple bond is adjacent to E, reaction of a compound of formula X as hereinbefore defined in which L3 represents L2 as hereinbefore defined (for example —B(OH)2) with a compound of formula XII,
E-Db-H XII
wherein Db represents —S—, —O— or C2-4 alkynylene in which the triple bond is adjacent to E and E is as hereinbefore defined. Such reactions may be performed under similar conditions to those described hereinbefore in respect of process step (ii) above, for example in the presence of a suitable catalyst system, such as Cu(OAc)2, a suitable base, such as triethylamine or pyridine, and an appropriate organic solvent, such as DMF or dichloromethane;
(xii) for compounds of formula I in which D represents —S(O)— or —S(O)2—, oxidation of a corresponding compound of formula I in which D represents —S—under appropriate oxidation conditions, which will be known to those skilled in the art;
(xiii) for compounds of formula I in which D represents —O— or —S—, reaction of a compound of formula XIII,
wherein the -Dc-H group is attached to one or both of the two carbon atoms of the thienoid ring of the thienopyrrole, Dc represents —O— or —S— and the dotted lines, U, V, X1, R1, R2-R3, R4 and Y are as hereinbefore defined, with a compound of formula XIV,
E-L2 XIV
wherein L2 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 (ii) above;
(xiv) for compounds of formula I in which X1 represents —N(R8)-J-R9, reaction of a compound of formula XV,
wherein the dotted lines, U, V, R1, R2, R4, Y and R8 are as hereinbefore defined, with a compound of formula XVI,
R9-J-L1 XVI
wherein J, R9 and L1 are as hereinbefore defined, for example at around room temperature or above (e.g. up to 60-70° C.) in the presence of a suitable base (e.g. pyrrolidinopyridine, pyridine, triethylamine, tributylamine, trimethylamine, dimethylaminopyridine, diisopropylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, sodium hydroxide, or mixtures thereof) and an appropriate solvent (e.g. pyridine, dichloromethane, chloroform, tetrahydrofuran, dimethylformamide, dimethylsulfoxide, water, triethylamine or mixtures thereof) and, in the case of biphasic reaction conditions, optionally in the presence of a phase transfer catalyst);
(xv) for compounds of formula I in which X1 represents —N(R8)-J-R9, J represents a single bond and R9 represents a C1-8 alkyl group, reduction of a corresponding compound of formula I, in which J represents —C(O)— and R9 represents H or a C1-7 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;
(xvi) for compounds of formula I in which X1 represents halo, reaction of a compound of formula I wherein X1 represents H, with a reagent or mixture of reagents known to be a source of halo atoms. For example, for Br 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-chlorosuccinimide may be employed, for Cl atoms, N-chlorosuccinimide may be employed and for F atoms, 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate), 1-fluoropyridinium triflate, xenon difluoride, CF3OF 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;
(xvii) for compounds of formula I in which R4 represents —OR12a in which R12a is other than H, reaction of a compound of formula XVII,
wherein L5 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, X1, R1, R2 and Y are as hereinbefore defined, with a compound of formula XVIII,
L6C(O)OR12za XVIII
wherein R12za represents R12a provided that it does not represent H, and L6 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 R4 represents —OR12a and R12a is H, reaction of a compound of formula XVII in which L5 represents either:
R12aOH XIX
wherein R12a 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;
(xx) for compounds of formula I ha which R4 represents —OR12a in which R12a represents H, hydrolysis of a corresponding compound of formula I in which R12a does not represent H under standard conditions;
(xxi) for compounds of formula I in which R4 represents —OR12a and R12a does not represent H:
HN(R12b)R13b XX
wherein R12b and R13b are as hereinbefore defined under standard conditions. For example, the reaction may be performed in the presence of a suitable coupling reagent (e.g. 1,1′-carbonyldiimidazole, N,N′-dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbo-diimide (or hydrochloride thereof), N,N′-disuccinimidyl carbonate, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluoro-phosphate, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexa-fluorophosphate, benzotriazol-1-yloxytris-pyrrolidinophosphonium hexa-fluorophosphate, bromotrispyrrolidinophosphonium hexafluorophosphate, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluorocarbonate or 1-cyclohexylcarbodiimide-3-propyloxymethyl polystyrene, O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate or O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate), and/or a suitable base (e.g. sodium hydride, sodium bicarbonate, potassium carbonate, pyrrolidinopyridine, pyridine, triethylamine, tributylamine, trimethylamine, dimethylaminopyridine, diisopropylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, sodium hydroxide, N-ethyldiisopropylamine, N-(methylpolystyrene)-4-(methylamino)pyridine, potassium bis(trimethylsilyl) amide, sodium bis(trimethylsilyl)amide, potassium tert-butoxide, lithium diisopropylamide, lithium 2,2,6,6-tetramethylpiperidine, butyllithium (e.g. n-, s- or t-butyllithium) or mixtures thereof) and an appropriate solvent (e.g. tetrahydrofuran, pyridine, toluene, dichloromethane, chloroform, acetonitrile, dimethylformamide, dimethylsulfoxide, water, triethylamine or mixtures thereof). Alternatively an azodicarboxylate may be employed under Mitsunobo conditions known to those skilled in the art. The skilled person will appreciate that it may be convenient or necessary to first convert the acid or ester compound of formula I to a corresponding acid halide prior to reaction with the compound of formula XX. Such conversions may be performed in the presence of a suitable reagent (e.g. oxalyl chloride, thionyl chloride, etc) optionally in the presence of an appropriate solvent (e.g. dichloromethane, THF, toluene or benzene) and a suitable catalyst (e.g. DMF), resulting in the formation of the respective acyl chloride. The skilled person will appreciate that when compounds of formula XX are liquid in nature, they may serve as both solvent and reactant in this reaction. An alternative way of performing this step, includes the reaction of a compound of formula I in which R4 represents —OR12a in which R12a 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);
(xxiii) for compounds of formula I in which X1 represents -Q-X2 and Q represents —O—, reaction of a compound of formula XXI,
wherein the dotted lines, U, V, R1, R2, R4 and Y are as hereinbefore defined, with a compound of formula XXII,
X2L7 XXII
wherein L7 represents a suitable leaving group, such as a halo or sulfonate group and X2 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;
(xxiv) for compounds of formula I in which X1 represents —N(R8)-J-R9, reaction of a compound of formula XXI as hereinbefore defined, with a compound of formula VI in which X1b represents —N(R8)-J-R9 and R8, R9 and J are as hereinbefore defined, for example under reaction conditions known to those skilled in the art (such as those described in Journal of Medicinal Chemistiy 1996, Vol. 39, 4044 (e.g. in the presence of MgCl2);
(xxv) for compounds of formula I in which X1 represents -Q-X2, Q represents a single bond and X2 represents C1-8 alkyl or heterocycloalkyl substituted α to the indole ring by a G1 substituent in which G1 represents -A1-R14a, A1 represents —OA5-, A5 represents a single bond and R14a represents H, reaction of a corresponding compound of formula I in which X1 represents H with a compound corresponding to a compound of formula VI, but in which X1b represents -Q-X2, Q represents a single bond and X2 represents C1-8 alkyl or heterocycloalkyl, both of which groups are substituted by a Z1 group in which Z1 represents ═O, under conditions known to those skilled in the art, for example optionally in the presence of an acid, such as a protic acid or an appropriate Lewis acid. Such substitutions are described in inter alia Bioorg. Med. Chem. Lett., 14, 4741-4745 (2004) and Tetrahedron Lett. 34,1529 (1993);
(xxvi) for compounds of formula I in which X1 represents -Q-X2, Q represents a single bond and X2 represents C2-8 alkyl substituted (e.g. α to the indole ring) by a G1 substituent in which G1 represents -A1-R14a, A1 represents —OA3-, A5 represents a single bond and R14a represents H, reaction of a corresponding compound of formula I in which X2 represents C1-7 alkyl substituted (e.g. a to the indole ring) by a Z1 group in which Z1 represents ═O, with the corresponding Grignard reagent derivative of a compound of formula V in which L2 represents chloro, bromo or iodo, Qa is a single bond and X2 represents C1-7 alkyl, under conditions known to those skilled in the art;
(xxvii) for compounds of formula I in which X1 represents -Q-X2, Q represents a single bond, and X2 represents C1-8 alkyl or heterocycloalkyl, both of which are unsubstituted in the position a to the indole ring, reduction of a corresponding compound of formula I in which X2 represents C1-8 alkyl substituted a to the indole ring by a G1 substituent in which G1 represents -A1-R14a, A1 represents —OA5-, A5 represents a single bond and R14a represents H, in the presence of a suitable reducing agent such as a mixture of triethyl silane and a protic acid (e.g. CF3COOH) or a Lewis acid (e.g. (CH3)3SiOS(O)2CF3) for example under conditions described in inter alia Bioorg. Med. Chem. Lett., 14, 4741-4745 (2004); or
(xxviii) for compounds of formula I in which X1 represents -Q-X2, Q represents a single bond and X2 represents C1-8 alkyl or heterocycloalkyl, neither of which are substituted by Z1 in which Z1 represents ═O, reduction of a corresponding compound of formula I in which X2 represents C1-8 alkyl or heterocycloalkyl, which groups are substituted by one or more Z1 groups in which Z1 represents ═O under conditions known to those skilled in the art, for example NaBH4 in the presence of an acid (e.g. CH3COOH or CF3COOH), Wolff-Kishner reduction conditions (i.e. by conversion of the carbonyl group to a hydrazone, followed by base induced elimination) or by conversion of the carbonyl to the thioacetal analogue (e.g. by reaction with a dithiane) followed by reduction with e.g. Raney nickel, all under reaction conditions known to those skilled in the art.
Compounds of formula II may be prepared by:
Compounds of formula IV may be prepared as follows:
R1L2 XXX
Compounds of formula VII may be prepared by:
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 L3 represents L2 may be prepared by reaction of a compound of formula X in which L3 represents L1, with an appropriate reagent for the conversion of the L1 group to the L2 group. This conversion may be performed by methods known to those skilled in the art, for example, compounds of formula X, in which L3 is 4,4,5,5-tetramethyl-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 L3 represents L1, for example under reaction conditions similar to those described hereinbefore in respect of preparation of compounds of formula I (process (ii)) above).
Compounds of formulae XV and XXVII may be prepared by reaction of a corresponding compound of formula IV, or XXIII, respectively, with a compound of formula XXXII,
R8NH2 XXXII
wherein R8 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).
Compounds of formulae XVII and XXVIII in which L5 represents an appropriate alkali metal, such as lithium may be prepared by reaction of a compound of formula XXXIII,
wherein Rz represents —Y—R1 (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, X1, Y, R1 and R2 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 L5 represents —Mg-halide may be prepared from a corresponding compound of formula XVII or XXVIII (as appropriate) in which L5 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 L5 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 L5 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.
Compounds of formula XXIII may be prepared by standard techniques. For example compounds of formula XXIII in which D represents a single bond, —C(O)—, —C(R6)(R7)—, C2-4 alkylene or —S(O)2— may be prepared by reaction of a compound of formula XXXIV,
wherein the dotted lines, U, V, L1, L3, R2-R3 and R4 are as hereinbefore defined with a compound of formula XI as hereinbefore defined, for example under reaction conditions similar to those described hereinbefore in respect of preparation of compounds of formula I (process (x)) above.
Compounds of formulae XXIV and XXXI, in which Q represents a single bond and X2a represents —CHO, may be prepared from compounds of formulae II, or X, respectively, in which X1 represents H, by reaction with a mixture of DMF and, for example, oxalyl chloride, phosgene or P(O)Cl3 (or the like) in an appropriate solvent system (e.g. DMF or dichloromethane) for example as described hereinbefore.
Compounds of formulae III, V, VI, VIII, IXA, IXB, IXC, XI, XII, XIII, XIV, XVI, XVIII, XIX, XX, XXI, XXII, XXV, XXVI, XXIX, XXX, XXXII, XXXIII and XXXIV are either commercially available, are known in the literature, or may be obtained either by analogy with the processes described herein, or by conventional synthetic procedures, in accordance with standard techniques, from available starting materials using appropriate reagents and reaction conditions. In this respect, the skilled person may refer to inter alia “Comprehensive Organic Synthesis” by B. M. Trost and I. Fleming, Pergamon Press, 1991.
Thienopyrroles of formulae II, IV, VII, X, XIII, XV, XVII, XXI, XXIII, XXIV, XXV, XXVI, XXVII, XXVIII, XXIX, XXXI, 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, 3rd edition, published by Chapman & Hall or “Comprehensive Heterocyclic Chemistry II” by A. R. Katritzky, C. W. Rees and E. F. V. Scriven, Pergamon Press, 1996) and/or made according to the following general procedures.
For example, compounds of formulae II, XXV and XXVI in which X1 represents H may be prepared by reaction of a compound of formula XXXV,
wherein 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,
N3CH2C(O)R4 XXXVI
wherein R4 is as hereinbefore defined and preferably —OR12a, in which R12a is as hereinbefore defined and preferably R12za as hereinbefore defined, under conditions known to the person skilled in the art (i.e. conditions to induce a condensation reaction, followed by a thermally induced cyclisation).
Compounds of formulae XXXV and XXXVI are either commercially available, are known in the literature, or may be obtained either by analogy with the processes described herein, or by conventional synthetic procedures, in accordance with standard techniques, from available starting materials using appropriate reagents and reaction conditions. In this respect, the skilled person may refer to inter alia “Comprehensive Organic Synthesis” by B. M. Trost and I. Fleming, Pergamon Press, 1991.
The substituents X1, R1, R2, R3 and R4 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 R4 represents —OR12a, in which R12a 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 final step), the relevant substituent may be hydrolysed to form a carboxylic acid functional group (in which case R12a will be hydrogen). In this respect, the skilled person may also refer to “Comprehensive Organic Functional Group Transformations” by A. R. Katritzky, O. Meth-Cohn and C. W. Rees, Pergamon Press, 1995.
Compounds of the invention may be isolated from then reaction mixtures using conventional techniques.
It will be appreciated by those skilled in the art that, in the processes described above and hereinafter, the functional groups of intermediate compounds may need to be protected by protecting groups.
The protection and deprotection of functional groups may take place before or after a reaction in the above-mentioned schemes.
Protecting groups may be removed in accordance with techniques that are well known to those skilled in the art and as described hereinafter. For example, protected compounds/intermediates described herein may be converted chemically to unprotected compounds using standard deprotection techniques.
The type of chemistry involved will dictate the need, and type, of protecting groups as well as the sequence for accomplishing the synthesis.
The use of protecting groups is fully described in “Protective Groups in Organic Chemistry”, edited by J W F McOmie, Plenum Press (1973), and “Protective Groups in Organic Synthesis”, 3rd edition, T. W. Greene & P. G. M. Wutz, Wiley-Interscience (1999).
Compounds of the invention are indicated as pharmaceuticals. According to a further aspect of the invention there is provided a compound of the invention, as hereinbefore defined but without proviso (a), for use as a pharmaceutical.
Although 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.
By “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.
Furthermore, certain compounds of the invention (including, but not limited to, compounds of formula I in which R4 represents —OR12a and R12a is other than hydrogen) 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 R4 represents —OR12a and R12a 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”.
Thus, 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 C4 (LTC4), 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 LTC4 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 Mol. Pharmacol., 41, 873-879 (1992).
Compounds of the invention are thus expected to be useful in the treatment of inflammation.
The term “inflammation” will be understood by those skilled in the art to include any condition characterised by a localised or a systemic protective response, which may be elicited by physical trauma, infection, chronic diseases, such as those mentioned hereinbefore, and/or chemical and/or physiological reactions to external stimuli (e.g. as part of an allergic response). Any such response, which may serve to destroy, dilute or sequester both the injurious agent and the injured tissue, may be manifest by, for example, heat, swelling, pain, redness, dilation of blood vessels and/or increased blood flow, invasion of the affected area by white blood cells, loss of function and/or any other symptoms known to be associated with inflammatory conditions.
The term “inflammation” will thus also be understood to include any inflammatory disease, disorder or condition per se, any condition that has an inflammatory component associated with it, and/or any condition characterised by inflammation as a symptom, including inter alia acute, chronic, ulcerative, specific, allergic and necrotic inflammation, and other forms of inflammation known to those skilled in the art. The term thus also includes, for the purposes of this invention, inflammatory pain, pain generally and/or fever.
Accordingly, 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. breast cancer, colon cancer, and prostate cancer), 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, iritis, 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.
Compounds of the invention are indicated both in the therapeutic and/or prophylactic treatment of the above-mentioned conditions.
According to a further aspect of the present invention, there is provided a method of treatment of a disease which is associated with, and/or which can be modulated by inhibition of, a member of the MAPEG family such as a PGES (such as mPGES-1), LTC4 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), LTC4 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.
“Patients” include mammalian (including human) patients.
The term “effective amount” refers to an amount of a compound, which confers a therapeutic effect on the treated patient. The effect may be objective (i.e. measurable by some test or marker) or subjective (i.e. the subject gives an indication of or feels an effect).
Compounds of the invention will normally be administered orally, intravenously, subcutaneously, buccally, rectally, dermally, nasally, tracheally, bronchially, sublingually, by any other parenteral route or via inhalation, in a pharmaceutically acceptable dosage form.
Compounds of the invention may be administered alone, but are preferably administered by way of known pharmaceutical formulations, including tablets, capsules or elixirs for oral administration, suppositories for rectal administration, sterile solutions or suspensions for parenteral or intramuscular administration, and the like.
Such formulations may be prepared in accordance with standard and/or accepted pharmaceutical practice.
According to a further aspect of the invention there is thus provided a pharmaceutical formulation including a compound of the invention, as hereinbefore defined 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).
According to a further aspect of the invention, there is provided a combination product comprising:
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).
Thus, there is further provided:
(1) 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
(2) a kit of parts comprising components:
Compounds of the invention may be administered at varying doses. Oral, pulmonary and topical dosages may range from between about 0.01 mg/kg of body weight per day (mg/kg/day) to about 100 mg/kg/day, preferably about 0.01 to about 10 mg/kg/day, and more preferably about 0.1 to about 5.0 mg/kg/day. For e.g. oral administration, the compositions typically contain between about 0.01 mg to about 500 mg, and preferably between about 1 mg to about 100 mg, of the active ingredient. Intravenously, the most preferred doses will range from about 0.001 to about 10 mg/kg/hour during constant rate infusion. Advantageously, compounds may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily.
In any event, the physician, or the skilled person, will be able to determine the actual dosage which will be most suitable for an individual patient, which is likely to vary with the route of administration, the type and severity of the condition that is to be treated, as well as the species, age, weight, sex, renal function, hepatic function and response of the particular patient to be treated. The above-mentioned dosages are exemplary of the average case; there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.
Compounds of the invention may have the advantage that they 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). The compounds of the invention may reduce the formation of the specific arachidonic acid metabolite PGE2 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.
In the assay mPGES-1 catalyses the reaction where the substrate PGH2 is converted to PGE2. mPGES-1 is expressed in E. coli and the membrane fraction is dissolved in 20 mM NaPi-buffer pH 8.0 and stored at −80° C. In the assay mPGES-1 is dissolved in 0.1M KPi-buffer pH 7.35 with 2.5 mM glutathione. The stop solution consists of H2O/MeCN (7/3), containing FeCl2 (25 mM) and HCl (0.15 M). The assay is performed at room temperature in 96-well plates. Analysis of the amount of PGE2 is performed with reversed phase HRLC (Waters 2795 equipped with a 3.9×150 mm C18 column). The mobile phase consists of H2O/MeCN (7/3), containing TFA (0.056%), and absorbance is measured at 195 nm with a Waters 2487 UV-detector.
The following is added chronologically to each well:
The invention is illustrated by way of the following examples, in which the following abbreviations may be employed:
AcOH acetic acid
DMF dimethylformamide
DMSO dimethylsulfoxide
EtOAc ethyl acetate
MeCN acetonitrile
NMR nuclear magnetic resonance
rt room temperature
TFA trifluoroacetic acid
THF tetrahydrofuran
Starting materials and chemical reagents specified in the syntheses described below are commercially available from, e.g. Sigma-Aldrich Fine Chemicals.
A solution of 5-bromothiophene-2-carboxaldehyde (9.55 g, 50.0 mmol) and azidoacetic acid ethyl ester (28.6 g, 200.0 mmol) in absolute EtOH (50 mL) was added to a stirred solution of NaOEt (2.3 M in EtOH, 87 mL, 200 mmol) in EtOH (100 mL). The mixture was stirred at −25° C. for 20 h and poured into NH4Cl (aq, sat) cooled to 0° C. The suspension was extracted with EtOAc. The combined extracts were washed with H2O and brine, dried (Na2SO4), concentrated and purified by chromatography to afford 2-azido-3-(4-bromothiophen-2-yl)acrylic acid ethyl ester as a yellow oil. The oil was dissolved in o-xylene (50 mL) which was added drop wise to o-xylene (50 mL) at reflux. After cooling, the precipitate was filtered off to give the sub-title compound (5.81 g, 36%)
A solution of NaI (1.8 g, 12.3 mmol) in acetone (100 mL) was added dropwise to a stirred solution of N-chlorosuccinimide (1.6 g, 12.3 mmol) in acetone (30 mL) protected from light, followed after 15 min by the dropwise addition of 2-bromo-thieno[3,2-b]pyrrole-5-carboxylic acid ethyl ester (2.8 g, 10.3 mmol; see step (a) above) in acetone (100 mL). After 30 min at rt the mixture was poured into Na2S2O3 (aq, 10%, 140 mL) and extracted with EtOAc. The combined extracts were washed with H2O and brine, dried (Na2SO4), concentrated and purified by chromatography to give the sub-title compound (3.78 g, 92%).
A solution of 2-bromo-6-iodothieno[3,2-b]pyrrole-5-carboxylic acid ethyl ester (400 mg, 1.0 mmol; see step (b) above) in DMF (4 mL) was added carefully to a stirred suspension of NaH (75% in mineral oil, 39 mg, 1.2 mmol) in DMF (2 mL) at 0° C. The mixture was stirred at 0° C. for 30 min. A solution of 1-bromo-3-phenylpropane (182 μL, 1.2 mmol) in DMF (4 mL) was added in portions. The mixture was stirred at rt for 12 h, poured into H2O and extracted with t-BuOMe. The combined extracts were washed with H2O and brine, dried (Na2SO4), concentrated and purified by chromatography to yield the sub-title compound (147 mg, 28%).
A mixture of 2-bromo-6-iodo-4-(3-phenylpropyl)thieno[3,2-b]pyrrole-5-carboxylic acid ethyl ester (147 mg, 0.28 mmol; see step (c)), aqueous NaOH (aq, 1 M, 1.5 mL) and MeCN (3.0 mL) was heated at 110° C. for 20 min. The mixture was allowed to cool, acidified with HCl (aq, 1M) to pH 2 and filtered. The solid was recrystallised from EtOH to give the title compound (55 mg, 40%).
200 MHz 1H NMR (acetone-d6, ppm) δ 11.7-11.2 (1H, br s) 7.46 (1H, s) 7.31-7.11 (5H, m) 4.67-4.59 (2H, m) 2.70-2.62 (2H, m) 2.21-2.08 (2H, m)
The title compound was prepared in accordance with Example 1, steps (c) and (d) from 2-bromo-6-iodothieno[3,2-b]pyrrole-5-carboxylic acid ethyl ester and (4-bromobutoxy)benzene.
200 MHz 1H NMR (DMSO-d6, ppm) δ 13.14 (1H, s) 7.77 (1H, s) 7.29-7.19 (2H, m) 6.92-6.84 (3H, m) 4.57-4.49 (2H, m) 3.90 (2H, t, J= 6.3 Hz) 1.88-1.72 (2H, m) 1.68-1.52 (2H, m).
The title compound was prepared in accordance with Example 1, steps (c) and (d) from 2-bromo-6-iodothieno[3,2-b]pyrrole-5-carboxylic acid ethyl ester and 1-bromo methyl-3,5-bis(trifluoromethyl)benzene.
200 MHz 1H NMR (acetone-d6, ppm) δ 11.8-11.4 (1H, br s) 7.96 (1H, s) 7.85 (2H, s) 7.70 (1H, s) 6.05 (2H, s).
The title compound was prepared in accordance with Preparation 1 from 4-bromothiophene-2-carboxaldehyde.
1H NMR (DMSO-d6, 200 MHz): δ 13.31 (1H, s) 7.75 (1H, s) 7.29-7.19 (2H, m) 6.92-6.84 (3H, m) 4.84-4.76 (2H, m) 3.93 (2H, t, J= 6.3 Hz) 1.95-1.80 (2H, m) 1.75-1.61 (2H, m).
2-Bromo-6-iodothieno[3,2-b]pyrrole-5-carboxylic acid ethyl ester (1.50 g, 3.75 mmol; see Preparation 1, step (b)) in DMF (10 mL) was added carefully to a stirred suspension of NaH (75% in mineral oil, 150 mg, 4.69 mmol) in DMF (10 mL) at 0° C. The mixture was stirred at 0° C. for 30 min and a solution of 3-chlorobenzyl chloride (595 μL, 4.69 mmol) in DMF (10 mL) was added in portions. The mixture was stirred at rt for 12 h, poured into H2O and extracted with t-BuOMe. The combined extracts were washed with H2O and brine, dried (Na2SO4), concentrated and recrystallised from MeOH to yield the sub-title compound (1.1 g, 57%).
2-Bromo-6-iodothieno[3,2-b]pyrrole-5-carboxylic acid ethyl ester (480 g, 1.2 mmol; see Preparation 1, step (b)), 3-chlorobenzyl chloride (0.23 g, 1.4 mmol), NaI (450 mg, 3 mmol), K2CO3 (410 mg, 2.8 mmol), and 18-crown-6 (22 mg, 0.1 mmol) were dissolved in anhydrous toluene (50 mL) and heated at reflux for 12 h. The mixture was filtered, concentrated and purified by chromatography to afford 470 mg (74%) of the sub-title compound.
K3PO4 (720 mg, 3.4 mmol), Pd(OAc)2 (22.4 mg, 0.1 mmol) and di-(tert-butyl)-bicyclohexylphosphine (53.6 mg, 0.18 mmol) were added to a solution of 2-bromo-4-(3-chlorobenzyl)-6-iodothieno[3,2-b]pyrrole-5-carboxylic acid ethyl ester (262.3 mg, 0.5 mmol; see step (a) above) and 4-trifluoromethoxy-phenylboronic acid (309 mg, 1.5 mmol) in toluene (10 mL). The mixture was heated at reflux for 14 h under argon, poured into Na2CO3 (aq, 10%, 50 ml) and extracted with EtOAc. The combined extracts were dried (MgSO4), concentrated and purified by chromatography, affording 173 mg (54%) of the sub-title product.
A mixture of 4-(3-chlorobenzyl)-2,6-bis-(4-trifluoromethoxyphenyl)thieno[3,2-b]-pyrrole-5-carboxylic acid ethyl ester (134 mg, 0.21 mmol; see step (b) above), KOH (aq, 1 M, 1.5 mL) and MeCN (5 mL) was heated at reflux for 24 h. The mixture was poured into H2O (10 mL) and acidified to pH 5 with HCl (aq, cone). The precipitate was filtered off and washed with H2O (100 mL) to yield 78 mg (61%) of the title compound.
200 MHz 1H-NMR (DMSO-d6, ppm) δ 12.75-12.55 (1H, br s) 7.97 (1H, s) 7.85-7.78 (2H, m) 7.73-7.67 (2H, m) 7.46-7.32 (7H, m) 7.19-7.11 (1H, m) 5.82 (2H, s).
The sub-title compound was prepared in accordance with Example 1, step (b) from 2-bromo-4-(3-chlorobenzyl)-6-iodothieno[3,2-b]pyrrole-5-carboxylic acid ethyl ester and 4-tert-butylphenylboronic acid.
A mixture of 2,6-bis-(4-tert-butylphenyl)-4-(3-chlorobenzyl)thieno[3,2-b]pyrrole-5-carboxylic acid ethyl ester (163 mg, 0.28 mmol; see step (a) above), KOH (aq, 2 M, 2.0 mL) and dioxane (3.0 mL) was heated by microwave irradiation at 120° C. for 5 h. The mixture was acidified with HCl (aq, cone) and the precipitate was filtered off and washed with H2O (50 mL) to yield 114 mg (73%) of the title compound.
200 MHz 1H-NMR (DMSO-d6, ppm) δ 12.75-12.55 (1H, br s) 7.80 (1H, s) 7.62-7.57 (2H, m) 7.51-7.27 (9H, m) 7.13-7.08 (1H, m) 5.79 (2H, s) 1.31 (9H, s) 1.27 (9H, s).
The sub-title compound was prepared in accordance with Example 2, step (b) from 2-bromo-4-(3-chlorobenzyl)-6-iodothieno[3,2-b]pyrrole-5-carboxylic acid ethyl ester (see Example 1, step (a) above).
SOCl2 (73 μL, 1.0 mmol) was added to 2-bromo-4-(3-chlorobenzyl)-6-iodo-thieno[3,2-b]pyrrole-5-carboxylic acid (487.0 mg, 0.97 mmol; see step (a) above) in CH2Cl2 and stirred for 2 h at rt. The mixture was concentrated and methoxyethylamine (105 μL, 1.2 mmol) in toluene (10 mL) was added. After stirring for 4 h at rt, the mixture was concentrated and purified by chromatography affording 193 mg (32%) of the sub-title compound.
Pd(PPh3)4 (12 mg, 0.01 mmol) was added to a solution of 2-bromo-4-(3-chloro-benzyl)-6-iodothieno[3,2-b]pyrrole-5-carboxylic acid (2-methoxy ethyl) amide (166.1 mg, 0.3 mmol; see step (b) above) and phenylethynyltrimethylstannane (185.4 mg, 0.7 mmol) in toluene (3.0 mL) and the mixture was heated at reflux for 2 h, poured into Na2CO3 (aq, sat, 20 mL) and extracted with EtOAc. The combined extracts were dried (MgSO4), concentrated and purified by chromatography to afford the title compound (59 mg, 36%).
1H-NMR (200 MHz DMSO-d6, ppm) δ 7.89-7.83 (1H, m) 7.64-7.58 (2H, m) 7.51-7.48 (2H, m) 7.39-7.34 (6H, m) 7.23-7.21 (2H, m) 7.15 (1H, s) 7.04-7.02 (2H, m) 5.83 (2H, s) 3.69-3.62 (2H, m) 3.51 (2H, t, J= 5.1 Hz) 3.16 (3H, s).
A mixture of 2-bromothieno[3,2-b]pyrrole-5-carboxylic acid ethyl ester (1.0 g, 3.6 mmol; see Preparation 1, step (a)), hexamethyldisilazane (1.7 mL, 8.0 mmol) and THF (4 mL) was heated at reflux for 2 h under argon. The mixture was concentrated and (5-methylthien-2-yl)tributylstannane (1.7 g, 4.4 mmol), Pd(PPh3)4 (250 mg, 0.22 mmol) and toluene (5 mL) were added. The mixture was heated at reflux for 3 h, poured into Na2CO3 (aq, sat, 20 mL) and extracted with EtOAc. The combined extracts were washed with H2O and, brine, dried (MgSO4), concentrated and purified by chromatography, yielding the sub-title compound (670 mg, 64%).
The sub-title compound was prepared in accordance with Preparation 1, step (b) from 2-(5-methylthien-2-yl)thieno[3,2-b]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-b]pyrrole-5-carboxylic acid ethyl ester (see step (b) above) and 3-chlorobenzyl chloride.
The title compound was prepared in accordance with Example 2, step (b) from 4-(3-chlorobenzyl)-6-iodo-2-(5-methylthien-2-yl)thieno[3,2-b]pyrrole-5-carboxylic acid ethyl ester (see step (c) above).
200 MHz 1H-NMR (DMSO-d6, ppm) δ 13.3-12.9 (1H, br s) 7.59 (1H, s) 7.34-7.32 (2H, m) 7.22 (1H, s) 7.16 (1H, d, J= 3.5 Hz) 7.04-6.97 (1H, m) 6.80 (1H, d, J=3.5 Hz) 5.81 (2H, s) 2.45 (3H, s).
The sub-title compound was prepared in accordance with Example 1, step (a) from 2-bromothieno[3,2-b]pyrrole-5-carboxylic acid ethyl ester (see Preparation 1, step (a)) and 3-chlorobenzyl chloride.
Pd(PPh3)4 (60 mg, 0.052 mmol) and AsPh3 (60 mg, 0.2 mmol) was added to a solution of 2-bromo-4-(3-chlorobenzyl)thieno[3,2-b]pyrrole-5-carboxylic acid ethyl ester (399 mg, 1.0 mmol; see step (a) above) and phenylethynyltrimethylstannane (318 mg, 1.2 mmol) in toluene (3 mL). The mixture was heated at reflux for 4 h, poured into Na2CO3 (aq, sat, 20 mL) and extracted with EtOAc. The combined extracts were washed with H2O and brine, dried (MgSO4), concentrated and purified by chromatography yielding the sub-title compound (370 mg, 88%)
A solution of 4-(3-chlorobenzyl)-2-phenylethynylthieno[3,2-b]pyrrole-5-carboxylic acid ethyl ester (120 mg, 0.29 mmol; see step (b) above) in dioxane (3 mL) and KOH (aq, 4 M, 1 mL, 4 mmol) was heated at reflux for 4 h. The mixture was acidified with HCl (aq, cone) and filtered. The solid was washed with water (50 mL) and recrystallised from EtOH to yield 86 mg (76%) of the title compound.
200 MHz 1H-NMR (DMSO-d6, ppm) δ 7.68 (1H, s) 7.56-7.53 (2H, m) 7.46-7.42 (3H, m) 7.36-7.33 (2H, m) 7.25 (1H, s) 7.22 (1H, s) 7.09-7.05 (1H, m) 5.78 (2H, s).
The title compound was prepared in accordance with Example 5, steps (b) and (c) from 2-bromo-4-(3-chlorobenzyl)thieno[3,2-b]pyrrole-5-carboxylic acid ethyl ester see step (a), Example 5) and cyclohex-1-enylethynyltrimethylstannane.
200 MHz 1H-NMR (DMSO-d6, ppm) δ 7.50 (1H, s) 7.40-7.29 (2H, m) 7.24-7.18 (2H, m) 7.07-7.01 (1H, m) 6.24-6.20 (1H, m) 5.73 (2H, s) 2.15-2.11 (4H, m) 2.61-2.54 (4H, m).
The title compound was prepared in accordance with Example 5, steps (b) and (c) from 2-bromo-4-(3-chlorobenzyl)thieno[3,2-b]pyrrole-5-carboxylic acid ethyl ester see step (a), Example 5) and (5-methylthien-2-yl)trimethylstannane.
200 MHz 1H-NMR (DMSO-d6, ppm) δ 12.61 (1H, s) 7.43 (1H, s) 7.34-7.31 (2H, m) 7.22-7.19 (2H, m) 7.13 (1H, d, J= 1.9 Hz) 7.05-7.02 (1H, m) 6.79 (1H, d, J=1.9 Hz) 5.77 (2H, s) 2.45 (3H, s).
The title compound was prepared in accordance with Example 5, steps (b) and (c) from 2-bromo-4-(3-chlorobenzyl)thieno[3,2-b]pyrrole-5-carboxylic acid ethyl ester see step (a), Example 5) and trimethyl-(4-methylthien-2-yl)stannane.
200 MHz 1H-NMR (DMSO-d6, ppm) δ 12.62 (1H, s) 7.49 (1H, s) 7.33-7.30 (2H, m) 7.22-7.02 (5H, m) 5.77 (2H, s) 2.20 (3H, s).
The sub-title compound was prepared in accordance with Example 1, step (a) from 2-bromothieno[3,2-b]pyrrole-5-carboxylic acid ethyl ester (see Preparation 1 (a)) and 3-bromobenzyl chloride.
A mixture of 2-bromo-4-(3-bromobenzyl)thieno[3,2-b]pyrrole-5-carboxylic acid ethyl ester (399 mg, 0.9 mmol; see step (a) above), tributyl-(4-methylthien-2-yl)stannane (852 mg, 2.2 mmol), Pd(PPh3)4 (60 mg, 0.052 mmol) and toluene (5 mL) was heated at reflux for 4 h, poured into Na2CO3 (aq, sat, 20 mL) and extracted with EtOAc. The combined extracts were washed with H2O and brine, dried (MgSO4), concentrated and purified by chromatography, yielding the sub-title compound (269 mg, 65%).
The title compound was prepared in accordance with Example 5, step (c) from 4-(3-bromobenzyl)-2-(4-methylthien-2-yl)thieno[3,2-b]pyrrole-5-carboxylic acid ethyl ester (see step (b) above).
200 MHz 1H-NMR (DMSO-d6, ppm) δ 7.49-7.05 (8H, m) 5.77 (2H, s) 2.21 (3H, s).
The sub-title compound was prepared in accordance with Example 1, step (a) from 2-bromothieno[3,2-b]pyrrole-5-carboxylic acid ethyl ester (see Preparation 1 (a)) and 4-bromobenzyl chloride.
A mixture of 2-bromo-4-(4-bromobenzyl)thieno[3,2-b]pyrrole-5-carboxylic acid ethyl ester (399 mg, 0.9 mmol; see step (a), Example 9), phenylethynyl trimethylstannane (583 mg, 2.2 mmol), Pd(PPh3)4 (60 mg, 0.052 mmol) and toluene (5 mL) was heated at reflux for 4 h under argon, poured into Na2CO3 (aq, sat, 20 mL) and extracted with EtOAc. The combined extracts were washed with H2O and brine, dried (MgSO4), concentrated and purified by chromatography, yielding the sub-title compound (297 mg, 68%).
The title compound was prepared in accordance with Example 5, step (c) from 2-phenylethynyl-4-(4-phenylethynylbenzyl)thieno[3,2-b]pyrrole-5-carboxylic acid ethyl ester (see step (b) above).
200 MHz 1H-NMR (DMSO-d6, ppm) δ 7.64-7.42 (14H, m) 7.19 (1H, s) 7.15 (1H, s) 5.81 (2H, s).
The title compound was prepared in accordance with Example 10, step (b) from 2-bromo-4-(4-bromobenzyl)thieno[3,2-b]pyrrole-5-carboxylic acid ethyl ester (see Example 10, step (a)) and (5-methylthien-2-yl)trimethylstannane, followed by hydrolysis in accordance with Example 5, step (c).
200 MHz 1H-NMR (DMSO-d6, ppm) δ 12.58 (1H, br s) 7.52 (1H, s) 7.48 (1H, s) 7.39 (1H, s) 7.22 (1H, d, J= 2.1 Hz) 7.15-7.11 (4H, m) 6.79-6.78 (2H, m) 5.77 (2H, s) 2.44 (6H, s).
The title compound was prepared in accordance with Example 10, step (b) from 2-bromo-4-(3-bromobenzyl)thieno[3,2-b]pyrrole-5-carboxylic acid ethyl ester (see Example 9, step (a)) and phenylethynyltrimethylstannane followed by hydrolysis in accordance with Example 5, step (c).
200 MHz 1H-NMR (DMSO-d6, ppm) δ 7.67 (1H, s) 7.56-7.51 (4H, m) 7.43-7.35 (9H, m) 7.25 (1H, s) 7.18-7.14 (1H, m) 5.80 (2H, s).
The title compound was prepared in accordance with Example 10, step (b) from 2-bromo-4-(3-bromobenzyl)thieno[3,2-b]pyrrole-5-carboxylic acid ethyl ester (see Example 9, step (a)) and (5-methylthiophen-2-yl)trimethyl stannane, followed by hydrolysis in accordance with Example 5 step (c).
200 MHz 1H-NMR (DMSO-d6, ppm) δ 12.59 (1H, s) 7.48-7.41 (3H, m) 7.34-7.21 (3H, m) 7.12 (1H, d, J= 3.3 Hz) 6.95 (1H, d, J=7.7 Hz) 6.82-6.78 (2H, m) 5.79 (2H, s) 2.45 (6H, s).
The sub-title compound was prepared in accordance with Example 1, step (a) from 2-bromothieno[3,2-b]pyrrole-5-carboxylic acid ethyl ester (see Preparation 1 (a)) and 2-bromobenzyl chloride.
The title compound was prepared in accordance with Example 10, step (b) from 2-bromo-4-(2-bromobenzyl)thieno[3,2-b]pyrrole-5-carboxylic acid ethyl ester (see step (a) above) and phenylethynyltrimethylstannane, followed by hydrolysis in accordance with Example 5, step (c).
200 MHz 1H-NMR (DMSO-d6, ppm) δ 7.66-7.61 (3H, m) 7.46-7.44 (9H, m) 7.34-7.30 (3H, m) 6.46-6.42 (1H, m) 6.03 (2H, s).
The title compound was prepared in accordance with Example 10, step (b) from 2-bromo-4-(2-bromobenzyl)thieno[3,2-o]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).
200 MHz 1H-NMR (DMSO-d6, ppm) δ 12.43 (1H, s) 7.40-7.37 (1H, m) 7.32-7.27 (1H, m) 7.24-7.21 (2H, m) 7.15-7.13 (2H, m) 7.10-7.08 (1H, m) 6.92 (1H, d, J=2.6 Hz) 6.78 (1H, d, J= 2.6 Hz) 6.32 (1H, d, J= 7.0 Hz) 5.88 (2H, s) 2.50 (3H, s) 2.44 (3H, s).
The title compound was prepared in accordance with Example 10, step (b) from 2-bromo-4-(2-bromobenzyl)thieno[3,2-b]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).
200 MHz 1H-NMR (DMSO-d6, ppm) δ12.46 (1H, s) 7.42-7.38 (1H, m) 7.32-7.18 (6H, m) 7.14-7.11 (2H, m) 6.33 (1H, m) 5.89 (2H, s) 2.30 (3H, s) 2.19 (3H, s).
A mixture of 2-bromo-4-(3-chlorobenzyl)thieno[3,2-b]pyrrole-5-carboxylic acid ethyl ester (400 mg, 1.0 mmol; see Example 5, step (a)), 3,5-bis(trifluoromethyl)-phenylboronic acid (567 mg, 2.2 mmol), K3PO4 (1.38 g, 6.5 mmol), Pd(OAc)2 (22 mg, 0.098 mmol) and 2-di(tert-butyl)phosphinobiphenyl (60 mg, 0.20 mmol) in toluene (10 mL) was heated at reflux for 14 h under argon, poured into Na2CO3 (aq, 10%, 50 ml) and extracted with EtOAc. The combined extracts were dried (Na2SO4), concentrated and purified by chromatography, affording 362 mg (68%) of the sub-title product.
The title compound was prepared in accordance with Example 5, step (c) from 2-[3,5-bis(trifluoromethyl)phenyl]-4-(3-chlorobenzyl)thieno[3,2-b]pyrrole-5-carboxylic acid ethyl ester (see step (a) above).
200 MHz 1H-NMR (DMSO-d6, ppm) δ 8.28-8.26 (3H, m) 8.03 (1H, s) 7.35-7.31 (3H, m) 7.20 (1H, s) 7.06-7.03 (1H, m) 5.79 (2H, s).
A mixture of 2-bromo-4-(4-bromobenzyl)thieno[3,2-b]pyrrole-5-carboxylic acid ethyl ester (443 mg, 1.0 mmol; see Example 10, step (a)), phenylboronic acid (366 mg, 3.0 mmol), Pd(OAc)2 (22.4 mg, 0.1 mmol), K3PO4 (1.49 g, 7.0 mmol), tri-o-tolylphosphine (65 mg, 0.2 mmol) and toluene (10 mL) was heated at reflux for 5 h under argon. The mixture was poured into NH4Cl (aq, 10%, 50 mL) and extracted with EtOAc. The combined extracts were dried (Na2SO4), concentrated and purified by chromatography, affording 197 mg (45%) of the sub-title product.
The title compound was prepared in accordance with Example 5, step (c) from 4-biphenyl-4-ylmethyl-2-phenylthieno[3,2-b]pyrrole-5-carboxylic acid ethyl ester (see step (a) above).
200 MHz 1H-NMR (DMSO-d6, ppm) δ 7.80 (1H, m) 7.71-7.58 (6H, m) 7.43-7.24 (9H, m) 5.85 (2H, s).
The title compound was prepared in accordance with Example 18, step (a) from 2-bromo-4-(3-bromobenzyl)thieno[3,2-b]pyrrole-5-carboxylic acid ethyl ester (see Example 9, step (a)) and 4-ethoxyphenylboronic acid, followed by hydrolysis in accordance with Example 5, step (c).
200 MHz 1H-NMR (DMSO-d6, ppm) δ 12.57 (1H, s) 7.67-7.47 (7H, m) 7.37-7.30 (1H, m) 7.21 (1H, s) 7.02-6.96 (5H, m) 5.83 (2H, s) 4.06 (4H, q, J=7.0 Hz) 1.33 (6H, t, J= 7.0 Hz).
n-BuLi (2.5 M in hexanes, 40 mL, 100 mmol) was added to 3-methylthiophene (9.7 mL, 100 mmol) in THF (100 mL) at −78° C. under argon. After 1 h, DMF (8.6 mL, 110 mmol) was added and the mixture was allowed to warm to rt. After 24 h at rt, HCl (aq, 1M, 50 mL) was added and the mixture was extracted with Et2O. The combined extracts were washed with brine, dried (MgSO4), concentrated and distilled to afford 4-methylthiophene-2-carboxaldehyde (11.4 g, 90%), which was dissolved in a mixture of CHCl3 (60 mL) and AcOH (60 mL). To the resulting solution, N-bromosucinimide (16.0 g, 90 mmol) was added in portions The mixture was stirred at rt for 12 h, poured into Na2CO3 (aq, 20%, 250 mL) and extracted with CH2Cl2. The combined extracts were washed with brine, dried (MgSO4), concentrated and recrystallised from hexanes with few drops of CH2Cl2 to yield the sub-title compound (15.1 g, 82%).
The sub-title compound was prepared in accordance with Preparation 1 (a) from 5-bromo-4-methylthiophene-2-carboxaldehyde (see step (a) above) and azido-acetic acid ethyl ester.
The sub-title compound was prepared in accordance with Example 1, step (a) from 2-bromo-3-methylthieno[3,2-b]pyrrole-5-carboxylic acid ethyl ester (see step (b) above) and 3-chlorobenzyl chloride.
The title compound was prepared in accordance with Example 5, step (b) from 2-bromo-4-(3-chlorobenzyl)-3-methylthieno[3,2-b]pyrrole-5-carboxylic acid ethyl ester (see step (c) above) and (4-isopropoxyphenyl)trimethylstannane, followed by hydrolysis accordance with Example 5, step (c).
1H-NMR (200 MHz DMSO-d6, ppm) δ 12.57 (1H, s) 7.39-7.30 (5H, m) 7.00-6.95 (3H, m) 6.85-6.82 (1H, m) 5.97 (2H, s) 4.64 (1H, m) 2.20 (3H, s) 1.27 (6H, d, J=5.9 Hz).
The title compound was prepared in accordance with Example 5, step (b) from 2-bromo-4-(3-chlorobenzyl)-3-methylthieno[3,2-b]pyrrole-5-carboxylic acid ethyl ester (see Example 20, step (c)) and phenylethynyltrimethylstannane, followed by hydrolysis in accordance with Example 5, step (c).
1H-NMR (200 MHz DMSO-d6, ppm) δ 7.55-7.52 (2H, m) 7.43-7.33 (5H, m) 7.26 (1H, s) 6.89 (1H, s) 6.83-6.80 (1H, m) 5.99 (2H, s) 2.34 (3H, s).
The title compound was prepared in accordance with Example 5, step (b) from 2-bromo-4-(3-chlorobenzyl)-3-methylthieno[3,2-b]pyrrole-5-carboxylic acid ethyl ester (see Example 20, step (c)) and (5-methylthiophen-2-yl)tributylstannane, followed by hydrolysis in accordance with Example 5, step (c).
1H-NMR (200 MHz DMSO-d6, ppm) δ 12.59 (1H, s) 7.39-7.25 (3H, m) 6.99-6.98 (2H, m) 6.83-6.81 (2H, m) 5.97 (2H, s) 2.44 (3H, s) 2.28 (3H, s).
The sub-title compound was prepared in accordance with Preparation 1, steps (a-c) from 4-bromothiophene-2-carboxaldehyde and azidoacetic acid ethyl ester (step (a)), followed by iodination (step (b)) and N-alkylation with 1-bromomethyl-3,5-bis(trifluoromethyl)benzene (step (c)).
A mixture of 4-[3,5-bis(trifluoromethyl)benzyl]-3-bromo-6-iodothieno[3,2-b]-pyrrole-5-carboxylic acid ethyl ester (300 mg, 0.48 mmol; see step (a) above), phenylboronic acid (175 mg, 1.44 mmol), K3PO4 (713 mg, 3.36 mmol), Pd(OAc)2 (5 mg, 0.024 mmol), tri-o-tolylphosphine (15 mg, 0.048 mmol) and toluene (10 mL) was stirred under argon at rt for 30 min and at 100° C. for 2 h. The mixture was cooled to rt and poured into NaHCC3 (aq, sat) and extracted with EtOAc. The combined extracts were washed with H2O and brine, dried (Na2SO4), concentrated and purified by chromatography affording the sub-title compound (130 g, 47%).
The title compound was prepared ha accordance with Preparation 1, step (d) from 4-[3,5-bis(trifluoromethyl)benzyl]-3,6-diphenylthieno[3,2-b]pyrrole-5-carboxylic acid ethyl ester.
1H NMR (acetone-d6, 200 MHz) δ 11.2 (1H, br s) 7.83 (1H, s) 7.70-7.62 (2H, m) 7.53-7.25 (9H, m) 7.23 (2H, s) 5.84 (2H, s).
A mixture of 3-bromothieno[3,2-b]pyrrole-5-carboxylic acid ethyl ester (617 mg, 2.25 mmol (see Preparation 1 (a)), 4-tert-butylphenylboronic acid (601 mg, 3.38 mmol), K3PO4 (1.44 g, 6.76 mmol), Pd(OAc)2 (49 mg, 0.23 mmol), 2,2′-bis(di-tert-butylphosphino)-1,1′-biphenyl (137 mg, 0.46 mmol) and toluene (15 mL) was stirred under argon at rt for 30 min, and at 100° C. for 1 h. The mixture was cooled to rt, poured into NaHCO3 (aq, sat) and extracted with EtOAc. The combined extracts were washed with H2O and brine, dried (Na2SO4), concentrated and purified by chromatography affording the sub-title compound (592 mg, 80%).
The sub-title compound was prepared in accordance with Preparation 1, step (b) from NaI (648 mg, 4.32 mmol), N-chlorosuccinimide (576 mg, 4.32 mmol) and 3-(4-tot-butylphenyl)thieno[3,2-b]pyrrole-5-carboxylic acid ethyl ester (590 mg, 1.80 mmol). Yield 829 mg (80%).
The title compound was prepared in accordance with Preparation 1, steps (c) and (d) from 3-(4-tert-butylphenyl)-2,6-diiodothieno[3,2-b]pyrrole-5-carboxylic acid ethyl ester (see step (b) above) and 1-bromomethyl-3,5-bis(trifluoromethyl)-benzene.
1H NMR (DMSO-d6, 200 MHz) δ13.5-13.1 (1H, br s) 7.91 (1H, s) 7.28-7.21 (2H, m) 7.04 (2H, s) 6.94-6.88 (2H, m) 5.45 (2H, s) 1.23 (9H, s).
The title compound was prepared in accordance with Preparation 1, steps (c) and (d) from 3-(4-tert-butylphenyl)-2,6-diiodothieno[3,2-b]pyrrole-5-carboxylic acid ethyl ester and 3-phenoxybenzylbromide.
1H NMR (DMSO-d6, 200 MHz) δ 13.4-13.0 (1H, br s) 7.38-7.28 (4H, m) 7.14-7.05 (2H, m) 6.99-6.93 (2H, m) 6.88-6.81 (2H, m) 6.72 (1H, dd, J=8.2, 2.2 Hz) 6.13 (1H, d, J= 7.8 Hz) 5.94-5.91 (1H, m) 5.34 (2H, s) 1.27 (9H, s).
The sub-title compound was prepared in accordance with Example 5, step (b) from 2-bromothieno[3,2-b]pyrrole-5-carboxylic acid ethyl ester (see Preparation 1, step (a)) and (4-isopropoxyphenyl)trimethylstannane.
An oven dried ACE® pressure tube was charged with 2-(4-isopropoxyphenyl)-thieno[3,2-b]pyrrole-5-carboxylic acid ethyl ester (165 mg, 0.5 mmol; see step (a) above), K3PO4 (223 mg, 1.05 mmol), 4-isopropoxyphenylbromide (130 mg, 0.6 mmol) and toluene (1.0 mL) and flushed with argon. A solution of CuI (22.9 mg, 0.12 mmol) and N,N′-dimethyl-1,2-diaminoethane (26 μL, 0.24 mmol) in toluene (1.0 mL) was added. The mixture was heated at 90° C. for 36 h, cooled, filtered through Celite® and the solids were washed with EtOAc. The combined liquids were washed with NH4OH (aq, sat) and brine, dried (Na2SO4), concentrated and purified by chromatography affording the sub-title compound (190 mg, 82%).
The title compound was prepared in accordance with Example 5, step (c) from 2,4-bis-(4-isopropoxyphenyl)thieno[3,2-b]pyrrole-5-carboxylic acid ethyl ester (see step (b) above).
200 MHz 1H-NMR (DMSO-d6, ppm) δ 13.0-11.5 (1H, br s) 7.58-7.51 (2H, m) 7.32-7.25 (2H, m) 7.24 (1H, s) 7.04 (1H, s) 7.00-6.93 (2H, m) 6.93-6.86 (2H, m) 4.64 (1H, m) 4.61 (1H, m) 1.30 (6H, d, J= 6.1 Hz) 1.24 (6H, d, J= 6.1 Hz).
The title compound was prepared in accordance with Example 26 from 2-(4-iso-propoxyphenyl)thieno[3,2-b]pyrrole-5-carboxylic acid ethyl ester (see Example 26, step (a)) and 5-bromo-2-isopropoxypyridine, followed by hydrolysis.
200 MHz 1H-NMR (DMSO-d6, ppm) δ 12.5-12.4 (1H, br s) 8.24 (1H, d, J= 2.7 Hz) 7.77 (1H, dd, J= 8.8, 2.7 Hz) 7.63-7.56 (2H, m) 7.34 (1H, s) 7.18 (1H, s) 6.96-6.90 (2H, m) 6.86 (1H, d, J= 8.8 Hz) 5.31 (1H, m) 4.64 (1H, septet, J=6.1 Hz) 1.35 (6H, d, J=6.2 Hz) 1.26 (6H, d, J= 6.1 Hz).
The title compound was prepared in accordance with Example 26 from 2-(4-iso-propoxyphenyl)thieno[3,2-b]pyrrole-5-carboxylic acid ethyl ester (see Example 26, step (a)) and 4-bromo-1-methyl-2-nitrobenzene, followed by hydrolysis.
200 MHz 1H-NMR (DMSO-d6, ppm) δ 12.55 (1H, s) 8.06 (1H, d, J= 2.1 Hz) 7.73 (1H, dd, J= 8.2, 2.1 Hz) 7.63-7.53 (3H, m) 7.37 (1H, s) 7.24 (1H, s) 6.95-6.87 (2H, m) 4.62 (1H, m) 2.59 (3H, s) 1.24 (6H, d, J= 6.0 Hz).
The title compound was prepared in accordance with Example 26 from 2-(4-iso-propoxyphenyl)thieno[3,2-b]pyrrole-5-carboxylic acid ethyl ester (see Example 26, step (a)) and 3-(4-bromophenyl)acrylic acid ethyl ester, followed by hydrolysis.
200 MHz 1H-NMR (DMSO-d6, ppm) δ 12.55-12.40 (2H, br s) 7.84-7.77 (2H, m) 7.68 (1H, d, J= 16.0 Hz) 7.61-7.54 (2H, m) 7.50-7.43 (2H, m) 7.34 (1H, s) 7.16 (1H, s) 6.95-6.88 (2H, m) 6.59 (1H, d, J= 16.0 Hz) 4.62 (1H, m) 1.24 (6H, d, J=6.0 Hz).
The title compound was prepared in accordance with Example 26 from 2-(4-iso-propoxyphenyl)thieno[3,2-b]pyrrole-5-carboxylic acid ethyl ester (see Example 26, step (a)) and 1-bromo-4-cyclopentyloxybenzene, followed by hydrolysis.
200 MHz 1H-NMR (DMSO-d6, ppm) δ 7.56-7.49 (2H, m) 7.26-7.19 (2H, m) 7.02 (1H, s) 6.96 (1H, s) 6.93-6.88 (4H, m) 4.86-4.78 (1H, m) 4.62 (1H, m) 1.96-1.60 (8H, m) 1.26 (6H, d, J= 6.0 Hz).
The title compound was prepared in accordance with Example 26 from 2-(4-iso-propoxyphenyl)thieno[3,2-Z)]pyrrole-5-carboxylic acid ethyl ester (see Example 26, step (a)) and 2-(4-bromophenoxy)-2-methylpropionic acid ethyl ester (prepared as described in J. Am. Chem. Soc, 77, 6644 (1955), followed by hydrolysis.
200 MHz 1H-NMR (DMSO-d6, ppm) δ 13.1-12.4 (2H, br s) 7.60-7.55 (2H, m) 7.36-7.30 (2H, m) 7.30 (1H, s) 7.07 (1H, s) 6.94-6.88 (4H, m) 4.63 (1H, m) 1.58 (6H, s) 1.26 (6H, d, J=6.0 Hz).
A mixture of 5-methyl-2-thienylmagnesium bromide (prepared from 2-bromo-5-methylthiophene (1.77 g, 10 mmol) and Mg (0.24 g, 10 mmol) in THF (50 mL)), 2-bromothiophene (0.86 g, 10 mmol), bis(diphenylphosphino)propane nickel dichloride (54 mg, 0.1 mmol) and THF (20 mL) was stirred at rt for 2 h and at reflux for 4 h. The mixture was poured into NH4Cl (aq, sat, 100 mL) and extracted with Et2O. The combined extracts were washed with brine, dried (MgSO4), concentrated and distilled under reduced pressure affording 1.53 g (85%) of 5-methyl-[2,2′]bithiophene, which was dissolved in CHCl3 (25 mL) and AcOH (25 mL). To this solution was added N-bromosuccinimide (1.6 g, 9.0 mmol) in portions over 1 h. The mixture was stirred at rt for 24 h, poured into Na2CO3 (aq, sat, 100 mL) and extracted with CH2Cl2. The combined extracts were washed with brine, dried (MgSO4, concentrated and crystallised from petroleum ether affording the sub-title compound (1.98 g, 90%).
The title compound was prepared in accordance with Example 26 from 2-(4-isopropoxyphenyl)thieno[3,2-b]pyrrole-5-carboxylic acid ethyl ester (see Example 26, step (a)) and 5-bromo-5′-methyl-[2,2′]bithiophenyl (see step (a) above), followed by hydrolysis.
200 MHz 1H-NMR (DMSO-d6, ppm) δ 7.60-7.53 (2H, m) 7.18 (1H, s) 7.11-7.05 (4H, m) 6.93-6.86 (2H, m) 6.78 (1H, dd, J= 3.4, 1.1 Hz) 4.62 (1H, m) 2.45 (3H, s) 1.25 (6H, d, J=6.0 Hz).
Anhydrous CH2Cl2 (10 mL), Et3N (340 μL, 2.43 mmol), pyridine (200 μL, 2.43 mmol) and 3 Å molecular sieves (ca. 1.0 g) were added to 2-bromothieno[3,2-b]-pyrrole-5-carboxylic acid ethyl ester (332 mg, 1.21 mmol; see Example 1 step (a)), Cu(OAc)2 (440 mg, 2.43 mmol), and 4-cyclopentyloxyphenylboronic acid (500 mg, 2.43 mmol). The mixture was stirred vigorously at rt for 36 h and filtered through Celite®. The solids were washed with EtOAc, and the combined liquids concentrated and purified by chromatography to afford the sub-title compound (356 mg, 72%).
2-Bromo-4-(4-cyclopentyloxyphenyl)thieno[3,2-b]pyrrole-5-carboxylic acid ethyl ester (248 mg, 0.57 mmol), (5-methylthiophen-2-yl)tributylstannane (232 mg, 0.6 mmol) and Pd(PPh3)4 (60 mg, 0.052 mmol) were dissolved in toluene (3 mL) and heated at reflux for 3 h. The mixture was poured into NH4Cl (aq, sat, 20 mL) and extracted with EtOAc. The combined extracts were washed with brine, dried (MgSO4), concentrated and purified by chromatography affording the sub-title compound (196 mg, 76%).
The title compound was prepared in accordance with Example 5, step (c) from 4-(4-cyclopentyloxyphenyl)-2-(5-methylthien-2-yl)thieno[3,2-b]pyrrole-5-carboxylic acid ethyl ester (see step (b) above).
200 MHz 1H-NMR (DMSO-d6, ppm) δ 12.35 (1H, s) 7.32-7.28 (2H, m) 7.28 (1H, s) 7.16 (1H, d, J= 3.66 Hz) 7.00-6.96 (2H, m) 6.84 (1H, s) 6.77 (1H, d, J=3.66 Hz) 4.90-4.82 (1H, m) 2.43 (3H, s) 1.98-1.62 (8H, m).
The title compound was prepared in accordance with Example 33 from 2-bromo-thieno[3,2-b]pyrrole-5-carboxylic acid ethyl ester (see Preparation 1 (a)), D 4-isopropoxyphenylboronic acid and (5-methylthien-2-yl)tributylstannane, followed by hydrolysis.
200 MHz 1H-NMR (DMSO-d6, ppm) δ 12.40-12.30 (1H, br s) 7.32-7.28 (3H, m) 7.17 (1H, d, J= 3.7 Hz) 7.02-6.97 (2H, m) 6.85 (1H, s) 6.77 (1H, d, J= 3.7 Hz) 4.73-4.61 (1H, m) 2.43 (3H, s) 1.32 (6H, d, J= 6.4 Hz).
AlCl3 (15 g, 0.112 mol) was added in portions over 2 h to a solution of thiophene-3-carboxaldehyde (5 g, 0.044 mol) in CH2Cl2 (150 mL) at rt. Br2 (2.13 mL, 0.041 mol) in CH2Cl2 (20 mL) was added drop wise. The mixture was heated at reflux for 6 h, cooled, poured into H2O (250 mL) and extracted with CH2Cl2. The combined extracts were washed with brine, dried (MgSO4), concentrated and distilled to yield the sub-title compound 5.4 g (64%).
The sub-title compound was prepared in accordance with Preparation 1, step (a) from 5-bromothiophene-3-carboxaldehyde (see step (a) above) and azidoacetic acid ethyl ester.
The sub-title compound was prepared in accordance with Example 1, step (a) from 2-bromothieno[2,3-b]pyrrole-5-carboxylic acid ethyl ester (see step (b) above) and 3-chlorobenzyl bromide.
The sub-title compound was prepared in accordance with Example 5, step (b) from 2-bromo-6-(3-chlorobenzyl)thieno[2,3-b]pyrrole-5-carboxylic acid ethyl ester (see step (c) above) and (4-isopropoxyphenyl)trimethylstannane.
The title compound was prepared in accordance with Example 5, step (c) from 6-(3-chlorobenzyl)-2-(4-isopropoxyphenyl)thieno[2,3-b]pyrrole-5-carboxylic acid ethyl ester (see step (d) above).
200 MHz 1H-NMR (DMSO-d6, ppm) δ 7.50-7.46 (2H, m) 7.40-7.35 (3H, m) 7.25 (1H, s) 7.16-7.12 (2H, m) 6.95-6.91 (2H, m) 5.72 (2H, s) 4.68-4.56 (1H, m) 1.25 (6H, d, J= 6.4 Hz).
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 (5-methylthiophen-2-yl)tributylstannane, followed by hydrolysis.
200 MHz 1H-NMR (DMSO-d6, ppm) δ 7.39-7.37 (2H, m) 7.25 (1H, s) 7.16-7.10 (3H, m) 7.00 (1H, d, J= 3.4 Hz) 6.74 (1H, d, J= 3.4 Hz) 5.72 (2H, s) 2.43 (3H, s).
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.
200 MHz 1H-NMR (DMSO-d6, ppm) δ 7.39-7.36 (2H, m) 7.26 (1H, s) 7.23 (1H, s) 7.16-7.12 (2H, m) 7.07-7.04 (2H, m) 5.72 (2H, s) 2.18 (3H, s).
The sub-title compound was prepared in accordance with Preparation 1, step (c) from 3-bromothieno[3,2-b]pyrrole-5-carboxylic acid ethyl ester (see Preparation 1, step (a)) and 1-bromomethyl-3,5-bis(trifluoromethyl)benzene.
2-Pyrrolidinone (82 μL, 0.54 mmol) and MeNHCH2CH2NHMe (28 μL, 0.27 mmol) were added to a mixture of 4-[3,5-bis(trifluoromethyl)benzyl]-3-bromothieno[3,2-b]pyrrole-5-carboxylic acid ethyl ester (450 mg, 0.90 mmol; see step (a) above), K3PO4 (400 mg, 1.88 mmol), CuI (8.6 mg, 0.45 mmol) and toluene (5 mL). The mixture was stirred at 110° C. for 48 h, cooled to rt and filtered through Celite®. The solids were washed with EtOAc and the combined liquids were concentrated and purified by chromatography to yield the sub-title compound (171 mg, 38%).
The title compound was prepared in accordance with Preparation 1, step (d) from 4-[3,5-bis(trifluoromethyl)benzyl]-3-(2-oxopyrrolidin-1-yl)thieno-[3,2-b]pyrrole-5-carboxylic acid ethyl ester.
1H NMR (DMSO-d6, 200 MHz) δ 12.86 (1H, s) 8.01 (1H, s) 7.55-7.52 (3H, m) 7.36 (1H, s) 5.87 (2H, s) 3.35-3.23 (2H, m) 2.30 (2H, t, J= 8.0 Hz) 1.89-1.71 (2H, m).
The following compounds are prepared in accordance with techniques described herein:
Title compounds of the examples were tested in the biological test described above and were found to exhibit 50% inhibition of mPGES-1 at a concentration of 10 μM or below. For example, the following representative compounds of the examples exhibited the following IC50 values:
Example 35: 4700 nM
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/GB2006/000188 | 1/19/2006 | WO | 00 | 9/23/2008 |
| Number | Date | Country | |
|---|---|---|---|
| 60644559 | Jan 2005 | US |
