Patent Application
20090048285
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 cardiovascular diseases are known to have inflammatory components adding to the symptomotology 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 bronchoconstrictors 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 hypothesized 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. International patent application WO 00/46198 also discloses indoles for potential use in the treatment of inflammation. However, pyrrolopyridines are neither mentioned nor suggested in any of these documents.
International patent application WO 95/33748 discloses various pyrrolopyridines for use in the treatment of cardiovascular and renal diseases. Compounds with aryl or heteroaryl groups attached to (a) the pyridine ring, via a linker or otherwise; and/or (b) the 1(N)-position of the pyrrole ring, are not specifically disclosed in this document.
P. J. Roy et al, Synthesis, 16 (2005), 2751-2757, N. Lachance et al, Synthesis, 15 (2005), 2571-2577 and Dropinski et al, Bioorganic and Medicinal Chemistry Letters, 15 (2005), 5035-5038 all discloses various pyrrolopyridines. However, there is no mention or suggestion in any of these documents of compounds in which the pyridine ring of the pyrrolopyridine is substituted with an aromatic group (via a linker or otherwise), nor do these documents suggest the use of such compounds as inhibitors of in PGES.
According to the invention there is provided a compound of formula I,
wherein
one of Y1, T2, Y3 and Y4 represents —N═ and the others respectively represent —C(R3)═, —C(R4)═ and —C(R5)═;
R2 represents —OR6a or —N(R6b)R7;
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—;
X2 represents:
(a) 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
(b) an aryl group or a heteroaryl group, both of which are optionally substituted by one or more substituents selected from A;
one of the groups R3, R4 and R5 represents -D-E and:
a) the other groups are independently selected from hydrogen, G1, an aryl group, a heteroaryl group (which latter two groups are optionally substituted by one or more substituents selected from A), C1-8 alkyl and a heterocycloalkyl group (which latter two groups are optionally substituted by one or more substituents selected from G1 and/or Z1); and/or
b) any two other groups which are adjacent to each other are optionally linked to form, along with two carbon atoms of the essential pyridine ring in the compound of formula I, a 3- to 8-membered ring, optionally containing 1 to 3 heteroatoms, which ring is itself optionally substituted by one or more substituents selected from halo, —R6c, —OR6d and ═O;
D represents a single bond, —O—, —C(R10)(R11)—, C2-4 alkylene, —C(O)— or —S(O)m—;
m represents, on each occasion when mentioned above, 0, 1 or 2;
R1 and E independently represent an aryl group or a heteroaryl group, both of which groups are optionally substituted by one or more substituents selected from A;
R6a, R6b, R6c, R6d, R7, R8 and R9 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; or
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 R6b and R7, and R8 and R9 (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 heteroatoms and/or 1 to 3 double bonds, which ring is optionally substituted by one or more substituents selected from G1 and/or Z1;
R10 and R11 independently represent H, halo or C16 allyl, which latter group is optionally substituted by halo, or R10 and R11 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;
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-R12a;
wherein A1 represents a single bond or a spacer group selected from —C(O)A2-, —S(O)2A3-, —N(R13a)A4- or —OA5-, in which:
A2 represents a single bond, —O—, —N(R13b)— or —C(O)—;
A3 represents a single bond, —O— or —N(R13c)5;
A4 and A5 independently represent a single bond, —C(O)—, —C(O)N(R13d)—, —C(O)O—, —S(O)2— or —S(O)2N(R13e)—;
Z1 represents, on each occasion when mentioned above, ═O, ═S, ═NOR12b, —NS(O)2N(R13f)R2, ═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;
G2 represents, on each occasion when mentioned above, halo, cyano, —N3, —NO2, —ONO2 or -A6-R14a;
wherein A6 represents a single bond or a spacer group selected from —C(O)A7-; —S(O)2A8-, N(R15a)A9- or —OA10-, in which:
A7 represents a single bond, —O—, —N(R15b)— or —C(O)—;
A8 represents a single bond, —O— or —N(R15c)—;
A9 and A10 independently represent a single bond, —C(O)—, —C(O)N(R15d)—, —C(O)O—, —S(O)2— or —S(O)2N(R15e)—;
Z2 represents, on each occasion when mentioned above, ═O, ═S, ═NOR14b, ═NS(O)2N(R15f)R14c, ═NCN or ═C(H)NO2;
R12a, R12b, R12c, R13a, R13b, R13c, R13d, R13e, R13f, R14a, R14b, R14c, R15a, R15b, R15c, R15d, R15e and R15f 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 R12a to R12c and R13a to R13f, and/or R14a to R14c and R15a to R15f, 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-R16a;
wherein A11 represents a single bond or a spacer group selected from —C(O)A12-, —S(O)2A13-, —N(R17a)A14- or —OA15-, in which:
A12 represents a single bond, —O—, —N(R17b)— or —C(O)—;
A13 represents a single bond, —O— or —N(R17c)—;
A14 and A15 independently represent a single bond, —C(O)—, —C(O)N(R17d)—, —C(O)O—, —S(O)2— or —S(O)2N(R17e)—;
Z3 represents, on each occasion when mentioned above, ═O, ═S, ═NOR16b, ═NS(O)2N(R17f)R16c, ═NCN or ═C(H)NO2;
R16a, R16b, R16c, R17a, R17b, R17c, R17d, R17e and R17f 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(R18a)R19a, —OR18b and ═O; and
iii) an aryl or heteroaryl group, both of which are optionally substituted by one or more substituents selected from halo, Cl4 allyl, —N(RISC)R19b and —OR18d; or any pair of 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 halo, C1-4 allyl, —N(R18e)R19c, —OR18f and ═O;
R18a, R18b, R18c, R18d, R18e, R18f, R19a, R19b and R19c 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,
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, 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 allynyl 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.
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-aziridinyl-[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-naphthridinyl 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, in four specific embodiments of the invention, any one of Y1, Y2, Y3 or Y4 represents —N═ and the others respectively represent —C(R3)═, —C(R4)═ and —C(R5)═.
The skilled person will appreciate that when one of the R3 to R5 groups represents -D-E and any two other adjacent groups are linked to form another ring, then in the case where Y2, for example, represents —N═, then only R4 and R5 may be linked.
For the avoidance of doubt, when a term such as “R3 to R5” is employed herein, this will be understood by the skilled person to mean R3, R4 and R5 inclusively.
As stated hereinbefore, any pair of R12a, to R12c and R13a to R13f may be linked as hereinbefore defined. For the avoidance of doubt, such R12a to R12c groups, and R13a to R13f groups may be attached to a single nitrogen atom (e.g. R12a, and R13a or R12c and R13f), which may form part of the ring.
Preferred compounds of the invention include those in which:
A represents G1 or C1-7 (e.g. C1-6) alkyl optionally substituted by one or more G1 groups;
X2 represents C1-6 alkyl or heterocycloalkyl, both of which are optionally substituted by one or more G1 and/or Z1 groups;
R8 represents H or C1-2 alkyl (e.g. methyl);
R9 represents H or, preferably, C1-6 (e.g. C1-3) alkyl, which alkyl group may be unsubstituted, but is preferably substituted by one or more (e.g. one) groups selected from G1, or an aryl group optionally substituted by one or more B groups; or R8 and R9 are linked to form a 4- to 7-membered (such as a 4- to 6- (e.g. 5- or 6-) membered) ring, which ring may, for example preferably, contain (in addition to the nitrogen atom and the 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;
G1 represents halo, cyano, —NO2 or -A1-R12a;
A1 represents a single bond or, preferably (e.g. in the case where Y4 represents —N═), —C(O)A2-, —N(R13a)A4- or —OA5-;
A2 represents —O—;
A4 and A5 independently represent a single bond, —C(O)—, —C(O)N(R13d)— or —C(O)O—;
R12a to R12c, independently represent hydrogen, an aryl group, a heteroaryl group, C1-6 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;
R13a to R13f independently represent C1-2 alkyl or, preferably, hydrogen;
Z1 represents ═NOR12b, ═NCN or, preferably, ═O;
R6a to R6d and R7 independently represent H or C1-3 alkyl optionally substituted by one or more halo (e.g. fluoro) groups;
G2 represents halo, —NO2 or -A -R14a;
A6 represents —N(R15a)A9- or —OA10-;
A9 represents —C(O)N(R15d)—, —C(O)O— or, more preferably, a single bond or —C(O)—;
A10 represents a single bond;
Z2 represents ═NOR14b, ═NCN or, more preferably, ═O;
G3 represents halo, —NO2 or -A11-R16a;
A11 represents a single bond or, more preferably, —N(R17a)— or —O—;
R16a to R16c independently represent an optionally substituted C1-6 alkyl or aryl group;
Z3 represents ═O;
J represents a single bond, —C(O)— or —S(O)2—;
when any one of R16a, R16b, R16c, R17a, R17b, R17c, R17d, R17e and R17f represents optionally substituted C1-6 alkyl, the optional substituent is one or more halo groups;
when any one of R18a, R18b, R18c, R18d, R18e, R18f, R19a, R19b and R19c represents optionally substituted C2— allyl, 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 E may represent include optionally substituted phenyl, naphthyl, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl (e.g 1-imidazolyl, 2-imidazolyl or 4-imidazolyl), oxazolyl, isoxazolyl, thiazolyl, pyridyl (e.g. 2-pyridyl, 3-pyridyl or 4-pyridyl), indazolyl, indolyl, indolinyl, isoindolinyl, quinolinyl, 1,2,3,4-tetrahydroquinolinyl, isoquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, quinolizinyl, benzofuranyl, isobenzofuranyl, chromanyl, benzothienyl, pyridazinyl, pyrimidinyl, pyrazinyl, indazolyl, benzimidazolyl, quinazolinyl, quinoxalinyl, 1,3-benzodioxolyl, tetrazolyl, benzothiazolyl, and/or benzodioxanyl, groups.
Preferred values of R1 and E include optionally substituted pyridyl (e.g. 2-pyridyl), phenyl or imidazolyl.
Optional substituents on R1, X2 (when X2 represents an aryl or heteroaryl group) and E groups are preferably selected from:
halo (e.g. fluoro, bromo or, preferably, chloro);
cyano;
—NO2;
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 t-butyl), n-pentyl, isopentyl, n-hexyl or isohexyl), cyclic (e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), part-cyclic (e.g. cyclopropylmethyl), unsaturated (e.g. 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 4-pentenyl or 5-hexenyl) and/or optionally substituted with one or more halo (e.g. fluoro) group (so forming, for example, fluoromethyl, difluoromethyl or, preferably, trifluoromethyl);
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;
—OR20; and
—N(R20)R21;
wherein R20 and R21 independently represent, on each occasion when mentioned above, H or linear, branched or cyclic C1-6 alkyl, such as methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, t-butyl, cyclobutyl, cyclopentyl or cyclohexyl (which alkyl groups are optionally substituted by one or more halo (e.g. fluoro) groups (to form e.g. a trifluoromethyl group)). Preferred values of such C1-6 alkyl groups when Y1 represents —N═ include methyl and isopropyl, when Y2 or Y4 represent —N═, isopropyl and cyclopropyl and when Y3 represents —N═, isopropyl.
Preferred values of R2 include —OR6a. Preferred values of R6a, R6b, R6c and R6d include H.
Preferably (and particularly so when Y2 or Y3 represent —N═), when X1 represents:
-Q-X2, then Q is a single bond;
-Q-X2, then X2 represents C1-4 allyl (e.g. isopropyl or, preferably, methyl or ethyl) optionally substituted by one or more G1 groups.
Preferably (when X1 represents —N(R8)-J-R9, then):
J represents —C(O)—;
R8 represents H; and/or
R9 represents H, C1-5 allyl (e.g. butyl), optionally substituted by one or more G1 groups, or a phenyl group, optionally substituted by one or more B groups; or R8 and R9 are linked together to form a propylene or a butylene chain to form, together with the nitrogen atom and the J group to which they are respectively attached, a 5- or 6-membered ring, such as an optionally substituted pyrrolidin-1-yl ring, e.g. a pyrrolidinon-1-yl ring.
Preferably,
B represents G2;
G2 represents halo (e.g. chloro).
More preferred compounds include those in which:
one of R3 and R4 represents -D-E and the other represents aryl (e.g. phenyl) optionally substituted by one or more A groups, or, more preferably, H or, for example in the case where Y2 represents —N═, G1. In the case where Y4 or Y3 represent —N═, R4 more preferably represents -D-E and R3 more preferably represents H. In the case where Y1 represents —N═, R3 more preferably represents -D-E and R4 more preferably represents H;
D represents —O— or, more preferably (e.g. in the case when Y2 or Y4 represent —N═), a single bond;
R5 represents H;
A represents G1 or C1-6 (e.g. C1-5) alkyl (e.g. t-butyl or, more preferably, methyl or (e.g. in the case when Y2 or Y4 represent —N═) cyclohexyl) optionally substituted by one or more G1 groups;
X1 represents H, halo (e.g. chloro or fluoro) or -Q-X2. It is more preferred that when Y3 represents —N═, then X1 represents H or halo (e.g. chloro or fluoro) and when Y2 represents —N═, then X1 represents -Q-X2 or, more preferably, H;
Q represents (e.g. in the case where Y1 or Y4 represents —N═)—S— or, e.g. preferably in the case where Y4 represents —N═, —O— or, preferably, a single bond;
X2 represents C1-4 alkyl (e.g. isopropyl or, for example preferably in the case where Y1 represents —N═, methyl or ethyl) optionally substituted by one or more G1 groups;
G1 represents cyano or, more preferably (e.g. in the case when Y2, Y3 or Y4 represent —N═), halo (e.g. chloro or fluoro) or -A1-R12a;
A4 and A5 independently represent a single bond;
R12a to R12c independently represent a phenyl group, a heteroaryl (such as tetrazolyl (e.g. 5-tetrazolyl), imidazolyl (e.g. 4-imidazolyl or 2-imidazolyl) or pyridyl (e.g. 3-pyridyl, 4-pyridyl or, especially, 2-pyridyl) group, both of which groups are optionally substituted by one or more G3 groups or, more preferably, H or a C1-4 alkyl (e.g. methyl or, more preferably isopropyl or cyclopropyl) group, which latter group is optionally substituted by one or more G3 groups;
G3 represents -A11-R16a or, more preferably, halo (e.g. fluoro);
A11 represents a single bond;
R16a to R16c independently represent C1-2 alkyl (e.g. methyl) optionally substituted by one or more fluoro atoms.
More preferred (particularly in the case where Y3, Y2 or Y1, represent —N═) compounds include those in which:
when X1 represents halo, it represents chloro or fluoro;
A1 represents a single bond or, more preferably in the case where Y2 or Y3 represent —N═, —OA5- or, e.g. in the case where Y2 represents —N═, —N(R13a)A4-;
R12a to R12c independently represent a phenyl group, a heteroaryl group as hereinbefore defined, or, more preferably, a C1-4 alkyl (e.g. methyl, more preferably (for example in the case where Y3 represents —N═), isopropyl or, e.g. in the case where Y2 represents —N═, cyclopropyl) group, all of which are optionally substituted by one or more G3 groups.
Values of R1 that may be mentioned include 4-cyclopropoxyphenyl, 4-cyclopentyloxphenyl and 4-isopropoxyphenyl.
Values of E that may be mentioned include 3-trifluoromethylphenyl or, more preferably, 5-trifluoromethylpyrid-2-yl, 4-cyclohexylphenyl, 3-chlorophenyl, and 4-trifluoromethylphenyl. 5-Trifluoromethylpyrid-2-yl and 4-cyclohexylphenyl are particularly preferred when D represents a single bond in the case when any one of Y2, Y3 or Y4 represents —N═. 3-Chlorophenyl is particularly preferred when D represents —O—. 5-Trifluoromethylpyrid-2-yl and 4-cyclohexylphenyl are particularly preferred when D represents —O— in the case when Y1 is —N═. 4-Trifluoromethylphenyl is particularly preferred when D represents a single bond.
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.
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 X1, R2, Y1, Y2, Y3 and Y4 are as hereinbefore defined, with a compound of formula III,
R1L1 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 is as hereinbefore defined, for example optionally in the presence of an appropriate metal catalyst (or a salt or complex thereof) such as Cu, Cu(OAc)2, CuI (or 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, isopropanol, ethanol, 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). This reaction may be carried out at room temperature or above (e.g. at a high temperature, such as the reflux temperature of the solvent system that is employed) or using microwave irradiation;
(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 L1, R1, R2, Y1, Y2, Y3 and Y4 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(diphenyl-phosphino)-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 and 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 infer 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-R12a, A1 represents —N(R13a)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 R1, R2, Y1, Y2, Y3 and Y4 are as hereinbefore defined under reductive amination conditions in the presence of a compound of formula VIII,
R12a(R13a)NH VIII
wherein R12a and R13a 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-R12a, A1 represents —N(R13a)A4-, A4 is a single bond and R12a and R13a 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 R12a and R13a 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 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-R12a, A1 represents —OA5- or —N(R13a)A4-, A4 and A5 both represent a single bond and R12a 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-R12a, in which A1 represents —OA5- or —N(R13a)A4-, A4 and A5 both represent a single bond and R12a 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 allyl, saturated cycloalkyl, saturated heterocycloalkyl, C2-8 alkenyl, cycloalkenyl or heterocycloalkenyl, 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(R10)(R11)—, 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 more of the carbon atoms of the pyridine ring of the pyrrolopyridine (i.e. one of the carbon atoms of —C(R3)═, —C(R4)═ and —C(R5)═, and in place of the R3, R4 or R5 substituents, as appropriate), R3-R5 represents whichever of the two other substituents on the pyridine ring, i.e. R3, R4 and R5, are already present in that ring, and X1, R1, R2, Y1 to Y4, R3, R4 and R5 are as hereinbefore defined, with a compound of formula XI,
E-Da-L4 XI
wherein Da represents a single bond, —C(O)—, —C(R10)(R11)—, C2-4 allylene or —S(O)2—, L4 represents L1 (when L3 is L2) or L2 (when L3 is L1) and L1, L2, E, R10 and R11 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(R10)(R11)—, 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 -Dcc-H group is attached to one or more of the carbon atoms of the pyridine ring of the pyrrolopyridine, DC represents —O— or —S— and X1, R1, R2, Y1 to Y4 and R3-R5 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 R1, R2, Y1 to Y4 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 Xl1 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 R2 represents —OR6a and R6a 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 X1, R1 and Y1 to Y4 are as hereinbefore defined, with a compound of formula XVIII,
L6C(O)OR6za XVIII
wherein R6za represents R6a 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 R2 represents —OR6a and R6a is H, reaction of a compound of formula XVII in which L5 represents either:
(xix) for compounds of formula I in which R2 represents —OR6a, reaction of a corresponding compound of formula XVII in which L5 is a suitable leaving group known to those skilled in the art (such as a sulfonate group (e.g. a triflate) or, preferably, a halo (e.g. bromo or iodo) group) with CO (or a reagent that is a suitable source of CO (e.g. Mo(CO)6 or CO2(CO)8)), in the presence of a compound of formula XIX,
R6aOH XIX
wherein R6a 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 in which R2 represents —OR6 and R6a represents H, hydrolysis of a corresponding compound of formula I in which R6a does not represent H under standard conditions;
(xxi) for compounds of formula I in which R2 represents —OR6a and R6a does not represent H:
(xxii) for compounds of formula I in which R2 represents —N(R6b)R7, reaction of a corresponding compound of formula I in which R2 represents —OR6a with a compound of formula XX,
HN(R6b)R7 XX
wherein R6b and R7 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-ethylcarbodiimide (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 hexafluoro-phosphate, bromotrispyrrolidinophosponium 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 R2 represents —OR6a in which R6a 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 in which Q represents —O—, reaction of a compound of formula XXI,
wherein R1, R2 and Y1 to Y4 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 Chemistry 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 allyl or heterocycloalkyl substituted u to the indole ring by a G1 substituent in which G1 represents -A1-R12a, A1 represents —OA5-, A5 represents a single bond and R12a 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-R12a, A1 represents —OA5-, A5 represents a single bond and R12a represents H, reaction of a corresponding compound of formula I in which X2 represents C1-7 alkyl substituted (e.g. α 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 α 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-R12a, A1 represents —OA5-, A5 represents a single bond and R12a 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:
(o) for compounds of formula II in which R2 represents —OR6a and R6a is other than H, reaction of a compound of formula XXVIII,
wherein R2 and Y1 to Y4 are as hereinbefore defined, with a compound of formula XXII as hereinbefore defined, for example under reaction conditions similar to those described hereinbefore in respect of preparation of compounds of formula I (process (xxiii)) above;
(v) for compounds of formula II in which X1 represents —N(R8)-J-R9, reaction of a compound of formula XXIX 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 conditions similar to those described hereinbefore in respect of preparation of compounds of formula I (process (xxiv)) above;
Compounds of formula IV may be prepared as follows:
R1L2 XXX
Compounds of formula VII may be prepared as follows:
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 XXII
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 R1 (in the case of a compound of formula XVII) or PG (in the case of a compound of formula XXVIII), and PG, X1, R3 and Y1 to Y4 are as hereinbefore defined, with an appropriate base, such 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(R10)(R11)—, C2-4 allylene or —S(O)2—, may be prepared by reaction of a compound of formula XXXIV,
wherein L1, L3, R2,Y1 to Y4 and R3-R5 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 represent 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.
Pyrrolopyridines 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, R2 represents —OR6a and R6a represents optionally substituted C1-8 (e.g. C1-6) alkyl may prepared by:
Compounds of formula XXXV may be prepared by reaction of a compound of formula XXXVIII,
wherein SUB and Y1 to Y4 are as hereinbefore defined with a compound of formula XXXIX,
(C(O)OR6zb)2 XXXIX
wherein R6zb is as hereinbefore defined, for example in the presence of an appropriate weak base (e.g. KOR6zb, such as KOEt).
Compounds of formula XXXVIIA may be prepared by reaction of a compound of formula XL,
wherein SUB and Y1 to Y4 are as hereinbefore defined, with a compound of formula XLI,
N3—CH2—C(O)OR6zb XLI
wherein R6zb is as hereinbefore defined, for example in the presence of a suitable base (such as an alkali metal ethoxide (e.g. NaOEt)) in the presence of an alcoholic solvent (e.g. ethanol) at below room temperature (e.g. 0° C.).
Compounds of formulae XXXVI, XXXVII, XXXVIII, XXXIX, XL and XLI 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. For example, compounds of formula XXXVIII in which SUB represents the substitution pattern of a compound of formula XXV, and one of e.g. R3, R4 or R5 represents -D-E and D represents —O— or —S—, may be prepared by reaction of a corresponding compound of formula XXXVIII in which L3 represents, for example, halo, with a compound of formula XII as hereinbefore defined or a phenol equivalent thereof (i.e. a compound of formula E-OH), under known 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, R4 and R5 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 R2 represents —OR6a and R6a 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 R6a 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 their 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 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 R2 represents —OR6a and R6a 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 R2 represents —OR6a and R6a 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, 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, 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:
(A) a compound of the invention, as hereinbefore defined; and
(B) another therapeutic agent that is useful in the treatment of inflammation, wherein each of components (A) and (B) is formulated in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier.
Such combination products provide for the administration of a compound of the invention in conjunction with the other therapeutic agent, and may thus be presented either as separate formulations, wherein at least one of those formulations comprises a compound of the invention, and at least one comprises the other therapeutic agent, or may be presented (i.e. formulated) as a combined preparation (i.e. presented as a single formulation including a compound of the invention and the other therapeutic agent).
Thus, there is further provided:
(1) a pharmaceutical formulation including a compound of the invention, as hereinbefore defined, another therapeutic agent that is useful in the treatment of inflammation, and a pharmaceutically-acceptable adjuvant, diluent or carrier; 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 in PGES-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 HPLC (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 LTV-detector.
The following is added chronologically to each well:
The invention is illustrated by way of the following examples. Starting materials and chemical reagents specified in the syntheses described below are commercially available from, e.g. Sigma-Aldrich Fine Chemicals.
Finely ground NaOH (106 mg, 2.66 mmol) was added to a solution of 2-chloro-4-methyl-5-nitropyridine (345 mg, 2.0 mmol) and 3-trifluoromethylplienol (270 μL, 2.2 mmol) in anhydrous MeCN (6 mL). The nature was heated at reflux for 4 h and cooled to rt. H2O (6 mL) was added and the mixture was extracted with EtOAc (3×15 mL). The combined extracts were washed with H2O and brine, dried (Na2SO4), concentrated and purified by chromatography to afford the sub-title compound (550 mg, 93%).
Potassium (126 mg, 3.2 mmol) was added under argon to a mixture of anhydrous Et2O (9 mL) and absolute EtOH (720 μL). After all potassium was dissolved, a solution of oxalic acid diethyl ester (450 μL, 3.3 mmol) in anhydrous Et2O (2 mL) was added via syringe. After 10 min, 4-methyl-5-nitro-2-(3-trifluoromethyl-phenoxy)pyridine (920 mg, 3.0 mmol; see step (a) above) in anhydrous Et2O (5 mL) was added and the mixture was stirred at rt for 48 h. The dark red precipitate was collected, washed with Et2O and dried. The solid was suspended in water (15 mL) and the pH was adjusted to 3-4 with AcOH. The mixture was extracted with CH2Cl2 (2×30 mL) and the combined extracts were washed with H2O and brine, dried (Na2SO4), concentrated and purified by chromatography to afford the sub-title compound (560 mg, 47%).
3-[5-Nitro-2-(3-trifluoromethoxyphenoxy)pyridin-4-yl]-2-oxopropionic acid ethyl ester (1.40 g, 3.5 mmol; see step (b) above) in EtOAc (14 mL) and EtOH (14 mL) was hydrogenated at ambient temperature and pressure over Pd—C (10%, 320 mg, 0.3 mmol) for 2 h. Filtration, concentration and purification by chromatography afforded the sub-title compound (1.01 g, 82%).
Anhydrous CH2Cl2 (80 mL), followed by Et3N (280 μL, 2.0 mmol) and pyridine (160 μL, 2.0 mmol) were added to 5-(3-trifluoromethylphenoxy)pyrrolo[2,3-c]pyridine-2-carboxylic acid ethyl ester (350 mg, 1.0 mmol; see step (c) above), Cu(OAc)2 (360 mg, 2.0 mmol), 4 Å molecular sieves (ca. 20 mg) and 4-isopropoxyphenylboronic acid (360 mg, 2.0 mmol). The mixture was stirred vigorously at rt for 72 h and filtered through Celite®. The solids were washed with EtOAc, and the filtrates concentrated and purified by chromatography to afford the sub-title compound (310 mg, 65%).
A mixture of 1-(4-isopropoxyphenyl)-5-(3-trifluoromethylphenoxy)pyrrolo[2,3-c]-pyridine-2-carboxylic acid ethyl ester (310 mg, 0.6 mmol, see step (d) above), NaOH (aq, 2 M, 2 mL) and dioxane (3 mL) was heated at 120° C. for 30 min. The mixture was diluted with H2O and acidified with HCl (aq, 1 M) to pH 5. The precipitate was collected and recrystallised from EtOH to give the title compound (170 mg, 63%).
200 MHz 1H-NMR (DMSO-d6, ppm) δ 13.34-13.29 (1H, br s) 8.12-8.09 (1H, m) 7.63-7.51 (1H, m) 7.49-7.41 (2H, m) 7.39-7.25 (5H, m) 7.06-6.98 (2H, m) 4.68 (1H, septet, J=5.9 Hz) 1.30 (6H, d, J=5.9 Hz).
BuLi (2.5 M in hexanes, 36 mL, 90 mmol) was slowly added to diisopropylamine (12.5 mL, 89.2 mmol) in THF (80 mL) at 0° C. The mixture was cooled to −80° C. and 2,6-dichloropyridine (12.0 g, 81.1 mmol) in THF (80 mL) was added over 70 min at −80° C. After 30 min, DMF (19 mL, 243 mmol) was added and the mixture was stirred for an additional 40 min at −80° C. NH4Cl (aq, sat) was added and the mixture was extracted with EtOAc. The combined extracts were dried (Na2SO4), concentrated and crystallised from hexane to give the sub-title compound (7.43 g 52%).
NaOEt (2.5 M in EtOH, 28.8 mL, 72 mmol) was added to 2,6-dichloropyridine-3-carboxaldehyde (3.17 g, 18.0 mmol; see step (a) above) and azidoacetic acid ethyl ester (9.3 g, 72 mmol) in EtOH (130 mL) at 0° C. during 40 min. After 3 h at 0° C., NH4Cl (aq, sat) was added and the mixture was extracted with EtOAc. The combined extracts were dried (Na2SO4), concentrated and purified by chromatography to afford the sub-title compound (1.7 g, 33%).
(Z)-2-Azido-3-(2,6-dichloropyridin-3-yl)acrylic acid ethyl ester (1.5 g, 5.23 mmol; see step (b) above) in mesitylene (15 mL) was added to mesitylene (50 mL) at reflux. After 1.5 h at reflux, the mixture was concentrated and the residue purified by chromatography to afford the sub-title compound (310 mg, 23%).
The sub-title compound was prepared in accordance with Example 1, step (d), from 4,6-dichloropyrrolo[3,2-c]pyridine-2-carboxylic acid ethyl ester (293 mg, 1.13 mmol; see step (c) above) and 4-isopropoxyphenylboronic acid (407 mg, 2.26 mmol), reaction time 8 h. Yield 373 g (84%).
A mixture of 4,6-dichloro-1-(4-isopropoxyphenyl)pyrrolo[3,2-c]pyridine-2-carboxylic acid ethyl ester (320 mg, 0.814 mmol) (step (d) above), 4-trifluoromethylphenylboronic acid (618 mg, 3.25 mmol), K3PO4 (1.20 g, 5.6 mmol), Pd(PPh3)4 (47 mg, 0.04 mmol) and toluene (3 mL) was stirred at 85° C. for 48 h. The mixture was cooled to rt, diluted with EtOAc, washed with H2O and brine, dried (Na2SO4), concentrated and purified by chromatography to afford the sub-title compound (281 mg, 56%).
A mixture of 1-(4-isopropoxyphenyl)-4,6-bis(4-trifluoromethylphenyl)pyrrolo-[3,2-c]pyridine-2-carboxylic acid ethyl ester (110 mg, 0.18 mmol; see step (e) above), NaOH (72 mg, 1.8 mmol), H2O (6 mL) and EtOH (4 mL) was stirred at reflux for 1.5 h. After cooling, the EtOH was partly evaporated, and the mixture was acidified with HCl (aq, 1 M) to pH 5 and extracted with EtOAc. The combined extracts were washed with brine, dried (Na2SO4), concentrated and purified by chromatography to give the title compound (100 mg, 95%).
200 MHz 1H-NMR (DMSO-d6, ppm) 13.4-13.0 (1H br s) 8.44-8.29 (4H, m) 8.06-7.94 (2H, m) 7.88-7.77 (2H, m) 7.68 (1H, s) 7.58 (1H, s) 7.46-7.36 (2H, m) 7.15-7.04 (2H, m) 4.74 (1H, septet, J=6.0 Hz) 1.36 (6H, d, J=6.0 Hz).
4,6-Dichloro-1-(4-isopropoxyphenyl)pyrrolo[3,2-c]pyridine-2-carboxylic acid ethyl ester (110 mg, 0.28 mmol) (step (d), Example 2), 4-trifluoromethyl-phenylboronic acid (319 mg, 1.68 mmol), Na2CO3 (aq, 2 M, 1.0 mL, 2.0 mmol), Pd(PPh3)4 (16 mg, 0.015 mmol), toluene (1 mL) and EtOH (0.23 mL) was stirred at 85° C. for 6 h. The mixture was cooled to rt, diluted with EtOAc, washed with H2O and brine, dried (Na2SO4), concentrated and purified by chromatography to afford the sub-title compound (70 mg, 49%).
The title compound was prepared in accordance with step ((e) in Example 1) from 6-chloro-1-(4-isopropoxyphenyl)-4-(4-trifluoromethylphenyl)pyrrolo[3,2-c]pyridine-2-carboxylic acid ethyl ester (see step (a) in above).
200 MHz 1H-NMR (DMSO-d6, ppm) δ 8.28-8.17 (2H, m) 7.99-7.88 (2H m) 7.05 (1H, s) 7.36-7.26 (2H, m) 7.09-6.96 (2H, m) 6.99 (1H, s) 4.68 (1H, m) 1.32 (6H, d, J=6.0 Hz).
A mixture of 2,6-dichloropyridine-3-carboxaldehyde (1.0 g, 5.68 mmol; see step (a) Example 2), 3-trifluoromethylphenol (3.68 g, 22.7 mmol), K2CO3 (3.99 g, 28.4 mmol), 18-crown-6 (150 mg, 0.57 mmol) and DMF (6 mL) was stirred at 60° C. for 3 h. The mixture was cooled to rt, diluted with H2O and extracted with t-BuOMe. The combined extracts were washed with H2O and brine, dried (Na2SO4) and concentrated. The residue was dissolved in 10 mL EtOH and this solution was slowly added to NaOH (aq, 10%) at 0° C. After 10 min, the precipitate was filtered off, washed with H2O and dried to afford the sub-title compound (1.15 g, 47%).
NaOEt (2.5 M in EtOH, 1.5 mL, 3.74 mmol) was added to 2,6-bis(3-trifluoromethylphenoxy)pyridine-3-carboxaldehyde (400 mg, 3.74 mmol; see step (a) above) and azidoacetic acid ethyl ester (483 mg, 3.74 mmol) in EtOH (1.7 mL) at 0° C. during 40 min. After 3 h at 0° C., NH4Cl (aq, sat) was added and the solid formed was filtered off, washed with H2O and dissolved in CH2Cl2. The solution was dried (MgSO4) and concentrated to give the sub-title compound (368 mg, 72%).
(Z)-2-Azido-3-[2,6-bis(3-trifluoromethylphenoxy)pyridin-3-yl]acrylic acid ethyl ester (290 mg, 0.54 mmol; see step (b) above) in xylene (1 mL) was added to xylene (4 μl) at reflux. After 1 h at reflux, the mixture was cooled to 0° C. and the precipitate collected and washed with cold xylene to afford the sub-title compound (156 mg, 57%).
The sub-title compound was prepared in accordance with step (d) in Example 1 from 4,6-bis(3-trifluoromethylphenoxy)pyrrolo[3),2-c]pyridine-2-carboxylic acid ethyl ester (see step (c) in above).
The title compound was prepared in accordance with step (e) in Example 1 from 1-(4-isopropoxyphenyl)-4,6-bis(3-trifluoromethylphenoxy)pyrrolo[3,2-c]pyridine-2-carboxylic acid ethyl ester (see step (d) in above).
200 MHz 1H-NMR (DMS O-d6, ppm) δ 7.60-7.49 (4H, m) 7.48-7.36 (3H, m) 7.31-7.24 (4H, m) 7.09-6.98 (2H, m) 6.33 (1H, s) 4.69 (1H, septet, J=6.0 Hz) 1.32 (6H, d, J=6.0 Hz).
The following compounds are prepared in accordance with techniques described herein:
1-(4-isopropoxyphenyl)-5-(4-trifluoromethylphenyl)pyqrolo [3,2-b]-pyridine-2-carboxylic acid;
Title compounds of the examples were tested in the biological test described above and were found to exhibit 50% inhibition of in mPGES-1 at a concentration of 10 μM or below. For example, the following representative compounds of the examples exhibited the following IC50 values:
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/GB06/00168 | 1/19/2006 | WO | 00 | 3/25/2008 |
| Number | Date | Country | |
|---|---|---|---|
| 60644526 | Jan 2005 | US | |
| 60644555 | Jan 2005 | US | |
| 60644556 | Jan 2005 | US | |
| 60644557 | Jan 2005 | US |
