Patent Application
20080188473
This invention relates to novel pharmaceutically-useful compounds, which compounds are useful as inhibitors of enzymes belonging to the membrane-associated proteins in the eicosanoid and glutathione metabolism (MAPEG) family. Members of the MAPEG family include the microsomal prostaglandin E synthase-1 (mPGES-1), 5-lipoxygenase-activating protein (FLAP), leukotriene C4 synthase and microsomal glutathione S-transferases (MGST1, MGST2 and MGST3). The compounds are of potential utility in the treatment of inflammatory diseases including respiratory diseases. The invention also relates to the use of such compounds as medicaments, to pharmaceutical compositions containing them, and to synthetic routes for their production
There are many diseases/disorders that are inflammatory in their nature. One of the major problems associated with existing treatments of inflammatory conditions is a lack of efficacy and/or the prevalence of side effects (real or perceived).
Inflammatory diseases that affect the population include asthma, inflammatory bowel disease, rheumatoid arthritis, osteoarthritis, rhinitis, conjunctivitis and dermatitis.
Inflammation is also a common cause of pain. Inflammatory pain may arise for numerous reasons, such as infection, surgery or other trauma. Moreover, several diseases including malignancies and cardioavascular diseases are known to have inflammatory components adding to the symptomatology of the patients.
Asthma is a disease of the airways that contains elements of both inflammation and bronchoconstriction. Treatment regimens for asthma are based on the severity of the condition. Mild cases are either untreated or are only treated with inhaled β-agonists which affect the bronchoconstriction element, whereas patients with more severe asthma typically are treated regularly with inhaled corticosteroids which to a large extent are anti-inflammatory in their nature.
Another common disease of the airways with inflammatory and bronchoconstrictive components is chronic obstructive pulmonary disease (COPD). The disease is potentially lethal, and the morbidity and mortality from the condition is considerable. At present, there is no known pharmacological treatment capable of changing the course of the disease.
The cyclooxygenase (COX) enzyme exists in two forms, one that is constitutively expressed in many cells and tissues (COX-1), and one that is induced by pro-inflammatory stimuli, such as cytokines, during an inflammatory response (COX-2).
COXs metabolise arachidonic acid to the unstable intermediate prostaglandin H2 (PGH2). PGH2 is further metabolised 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 hypothesised that better control of asthma, and possibly also COPD, may be attained if the activity of both of the CysLT receptors could be reduced. This may be achieved by developing unselective LTRas, but also by inhibiting the activity of proteins, e.g. enzymes, involved in the synthesis of the CysLTs. Among these proteins, 5-lipoxygenase, 5-lipoxygenase-activating protein (FLAP), and leukotriene C4 synthase may be mentioned. A FLAP inhibitor would also decrease the formation of the proinflammatory LTB4.
mPGES-1, FLAP and leukotriene C4 synthase belong to the membrane-associated proteins in the eicosanoid and glutathione metabolism (MAPEG) family. Other members of this family include the microsomal glutathione S-transferases (MGST1, MGST2 and MGST3). For a review, c.f. P.-J. Jacobsson et al in Am. J. Respir. Crit. Care Med. 161, S20 (2000). It is well known that compounds prepared as antagonists to one of the MAPEGs may also exhibit inhibitory activity towards other family members, c.f. J. H Hutchinson et al in J. Med. Chem. 38, 4538 (1995) and D. Claveau et al in J. Immunol. 170, 4738 (2003). The former paper also describes that such compounds may also display notable cross-reactivity with proteins in the arachidonic acid cascade that do not belong to the MAPEG family, e.g. 5-lipoxygenase.
Thus, agents that are capable of inhibiting the action of in PGES-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.
Various indole-2-carboxylates, and derivatives thereof, have been disclosed in international patent applications WO 01/30343, WO 96/03377, WO 01/00197 and WO 99/33800, U.S. Pat. Nos. 5,189,054 and 4,960,786, European patent application EP 483 881 and Italian Patent No. 1303260. However, none of these documents disclose or suggest the use of the indole-2-carboxylates in the treatment of inflammation.
Similar indole-2-carboxylates have been disclosed for potential use in the treatment of inflammation in international patent applications WO 99/07678, WO 99/07351, WO 00/46198, WO 00/46197, WO 00/46195, WO 00/46199, WO 96/18393, WO 02/30895, WO 99/05104, WO 01/32621 and WO 2005/005415, U.S. Pat. Nos. 5,081,145 and 5,081,138 and European patent applications EP 166 591 and EP 985 666. However, none of these documents disclose such compounds in which an aromatic group is directly attached to the ring system via the indole nitrogen.
International patent application WO 94/13662 and European patent application EP 186 367 also mention indoles for potential use in the treatment of inflammation. However, these documents do not mention or suggest compounds in which the benzenoid moiety of the indole is substituted with an aromatic ring.
International patent applications WO 94/14434, WO 99/43672, WO 98/08818, WO 99/43654 and WO 99/43651 and U.S. Pat. Nos. 6,500,853 and 6,630,496 also describe structurally similar indoles for such potential use. However, there is no specific disclosure in any of these documents of indole-2-carboxylates in which an aromatic group is directly attached via the indole nitrogen.
According to the invention there is provided a compound of formula I,
wherein
X represents a single bond, —C(O)— or —S(O)2—.
R1 represents an aryl group or a heteroaryl group, both of which groups are optionally substituted by one or more substituents selected from A;
one of the groups R2, R3, R4 and R5 represents an aryl group or a heteroaryl group (both of which are optionally substituted by one or more substituents selected from A) 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 atoms of the essential benzene ring in the compound of formula I, a 3- to 8-membered ring, optionally containing 1 to 3 heteroatoms and/or 1 to 3 double bonds, which ring is itself optionally substituted by one or more substituents selected from halo, —R8, —OR8 and ═O;
R6, R7 and R8 independently represent, on each occasion when used above:
I) hydrogen;
II) an aryl group or a heteroaryl group, both of which are optionally substituted by one or more substituents selected from B;
III) C1-8 alkyl or a heterocycloalkyl group, both of which are optionally substituted by one or more substituents selected from G1 and/or Z1; or
R6 and R7 may be linked together to form along with the N atom and X group to which R6 and R7 are respectively 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;
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;
III) a G1 group; or
IV) two A substituents may be linked together to form, along with at least two (e.g. adjacent) atoms of the aryl or heteroaryl group to which the two A substituents are attached, a further 3- to 5-membered ring, which ring optionally contains 1 to 3 (e.g. 1 or 2) heteroatoms and/or 1 to 2 (e.g. 1) double bonds, and which is optionally substituted by halo or C1-8 alkyl, which latter group is optionally substituted by halo;
G1 represents, on each occasion when mentioned above, halo, cyano, —N3, —NO2, —ONO2 or -A1-R9;
wherein A1 represents a single bond or a spacer group selected from —C(O)A2-, —S(O)nA3-, —N(R10)A4- or —OA5-, in which:
A2 and A3 independently represent a single bond, —O—, —N(R10)— or —C(O)—;
A4 and A5 independently represent a single bond, —C(O)—, —C(O)N(R10)—, —C(O)O—, —S(O)n— or —S(O)nN(R10)—;
Z1 represents, on each occasion when mentioned above, ═O, ═S, ═NOR9, ═NS(O)nN(R10)(R9), ═NCN or ═C(H)NO;
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, methylenedioxy, difluoromethylenedioxy and/or dimethylmethylenedioxy;
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;
III) a G2 group; or
IV) methylenedioxy, difluoromethylenedioxy or dimethylmethylenedioxy;
G2 represents, on each occasion when mentioned above, halo, cyano, —N3, —NO2, —ONO2 or -A6-R11;
wherein A6 represents a single bond or a spacer group selected from —C(O)A7-, —S(O)nA8-, —N(R12)A9- or —OA10-, in which:
A7 and A8 independently represent a single bond, —O—, —N(R21)— or
A9 and A10 independently represent a single bond, —C(O)—, —C(O)N(R12)—, —C(O)O—, —S(O)n— or —S(O)nN(R12);
Z2 represents, on each occasion when used above, ═O, ═S, ═NOR11, ═NS(O)nN(R12)(R11), ═NCN or ═C(H)NO2;
R9, R10, R11 and R12 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, methylenedioxy, difluoromethylenedioxy and/or dimethylmethylenedioxy;
iii) C1-8 alkyl or a heterocycloalkyl group, both of which are optionally substituted by G3 and/or Z3; or
any pair of R9 and R10, or R11 and R12, 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-R13;
wherein A11 represents a single bond or a spacer group selected from —C(O)A12-, —S(O)nA13, —N(R14)A14- or —OA15-, in which:
A12 and A13 independently represent a single bond, —O—, —N(R14)— or —C(O)—;
A14 and A15 independently represent a single bond, —C(O)—, —C(O)N(R14)—, —C(O)O—, —S(O)n— or —S(O)nN(R14)—;
Z3 represents, on each occasion when mentioned above, ═O, ═S, ═NOR3, ═NS(O)nN(R14)(R13), ═NCN or ═C(H)NO2;
n represents, on each occasion when mentioned above, 1 or 2;
R13 and R14 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(R15)(R16), —O(R15) and ═O; and
iii) an aryl or heteroaryl group, both of which are optionally substituted by one or more substituents selected from halo, C1-4 alkyl, —N(R15)(R16) and —O(R15); or
any pair R13 and R14 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 alkyl, —N(R15)(R16), —O(R15) and ═O;
R15 and R16 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 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 a C3-q cycloalkyl group). C3-q cycloalkyl groups that may be mentioned include monocyclic or bicyclic alkyl groups, which cycloalkyl groups may further be bridged. 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 groups may also be saturated or, when there is a sufficient number (i.e. a minimum of two) of carbon atoms, be unsaturated (forming, for example, a C3-q cycloalkenyl, a C8 cycloalkynyl or, more particularly, a C2-q alkenyl or a C2-q alkynyl 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 those 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 (e.g. C3-q) heterocycloalkenyl (where q is the upper limit of the range) or a C3-q heterocycloalkynyl group. C2-q heterocycloalkyl groups that may be mentioned include 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, oxetanyl, oxiranyl, piperazinyl, piperidinyl, pyranyl, pyrazolidinyl, pyrrolidinonyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, sulfolanyl, 3-sulfolenyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydropyridyl, thietanyl, thiiranyl, thiolanyl, thiomorpholinyl, trithianyl (including 1,3,5-trithianyl), tropanyl and the like. Other heterocycloalkyl groups that may be mentioned include 7-azabicyclo[2.2.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl, 6-azabicyclo-[3.2.1]octanyl, 8-azabicyclo[3.2.1]-octanyl, 7-oxabicyclo[2.2.1]heptanyl and 6-oxabicyclo[3.2.1]octanyl. Heterocycloalkyl groups that may be mentioned include monocyclic and bicyclic heterocycloalkyl groups, which groups may further be bridged. 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 C6-13 (e.g. C6-10) aryl groups. Such groups may be monocyclic or bicyclic and have between 6 and 13 (e.g. 10) ring carbon atoms, in which at least one ring is aromatic. C6-13 aryl groups include phenyl, naphthyl and the like, such as fluorenyl and, more particularly, 1,2,3,4-tetrahydronaphthyl, indanyl, and indenyl. 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 preferably linked to the rest of the molecule via an aromatic ring.
Heteroaryl groups that may be mentioned include those which have between 5 and 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 acridinyl, benzimidazolyl, benzodioxanyl, benzodioxepinyl, benzodioxolyl (including 1,3-benzodioxolyl), benzofuranyl, benzofurazanyl, benzothiazolyl (including 2,1,3-benzothiazolyl), benzoxadiazolyl (including 2,1,3-benzoxadiazolyl), benzoxazinyl (including 3,4-dihydro-2H-1,4-benzoxazinyl), benzoxazolyl, benzimidazolyl, 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 1,5-naphthyridinyl and 1,8-naphthyridinyl), oxadiazolyl (including 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl and 1,3,4-oxadiazolyl), oxazolyl, phenazinyl, phenothiazinyl, phthalazinyl, pteridinyl, purinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinolizinyl, quinoxalinyl, tetrahydroisoquinolinyl (including 1,2,3,4-tetrahydroisoquinolinyl and 5,6,7,8-tetrahydroisoquinolinyl), tetrahydroquinolinyl (including 1,2,3,4-tetrahydroquinolinyl and 5,6,7,8-tetrahydroquinolinyl), tetrazolyl, thiadiazolyl (including 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl and 1,3,4-thiadiazolyl), thiazolyl, thiochromanyl, thienyl, triazolyl (including 1,2,3-triazolyl, 1,2,4-triazolyl and 1,3,4-triazolyl) and the like. Substituents on heteroaryl groups may, where appropriate, be located on any atom in the ring system including a heteroatom. The point of attachment of heteroaryl groups may be via any atom in the ring system including (where appropriate) a heteroatom (such as a nitrogen atom), or an atom on any fused carbocyclic ring that may be present as part of the ring system. However, when heteroaryl groups are bicyclic or tricyclic, they are preferably linked to the rest of the molecule via an aromatic ring. Heteroaryl groups may also be in the N- or S-oxidised form.
Heteroatoms that may be mentioned include phosphorus, silicon, boron, tellurium, preferably, selenium and, more preferably oxygen, nitrogen and/or sulfur.
For the avoidance of doubt, optionally substituted methylenedioxy groups, when attached to a ring system, are formed between any two adjacent atoms of the ring system.
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 any one of R2 to R5, both represent 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 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.
Compounds of the invention that may be mentioned include those in which:
A2 and A3 independently represent a single bond, —O— or —N(R10)—;
Z1 represents, on each occasion when mentioned above, ═O, ═NOR9, ═NS(O)nN(R10)(R9), ═NCN or ═C(H)NO2;
A7 and A8 independently represent a single bond, —O— or —N(R12)—.
Z2 represents, on each occasion when mentioned above, ═O, ═NOR11, ═NS(O)nN(R12)(R11), ═NCN or ═C(H)NO2;
A12 and A13 independently represent a single bond, —O— or —N(R14)—; and/or
Z3 represents, on each occasion when mentioned above, ═O, ═NOR3, ═NS(O)nN(R14)(R13), ═NCN or ═C(H)NO2.
Preferred compounds of the invention include those in which:
X represents a single bond or —C(O)—;
G1 represents halo, cyano, —N3, —NO2 or -A1-R9;
A4 and A5 independently represent a single bond, —C(O)—, —C(O)N(R10)— or —C(O)O—;
Z1 represents ═NOR9, ═NCN or, preferably, ═O;
G2 represents cyano, —N3 or, more preferably, halo, —NO2 or -A6-R11;
A6 represents —N(R12)A9- or —OA10-;
A9 represents —C(O)N(R12)—, —C(O)O— or, more preferably, a single bond or —C(O)—;
A10 represents A and, preferably, a single bond;
Z2 represents ═NOR11 or ═NCN or, more preferably, ═O;
G3 represents halo, —NO, or -A11-R13;
A11 represents —N(R14)— or —O—;
Z3 represents ═O—;
n represents 2;
when either of R13 and R14 represent optionally substituted C1-6 alkyl, the optional substituent is one or more halo groups;
when either of R15 and R16 represent optionally substituted C1-4 alkyl, the optional substituent is one or more fluoro groups.
Preferred compounds of the invention include those in which R1 and (when they represent an aryl or heteroaryl group) R2, R3, R4 and/or R5 represent an 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, benzothiazolyl, and/or benzodioxanyl, group. Other groups that may be mentioned include optionally substituted 5,6,7,8-tetrahydroquinolinyl, 5,6,7,8-tetrahydroisoquinolinyl and tetrazolyl. Particularly preferred values include optionally substituted phenyl and pyridyl groups.
More preferred compounds include those in which:
R6 represents H or optionally substituted C1-6 alkyl;
R7 represents optionally substituted heteroaryl or, more preferably, optionally substituted C1-6 alkyl or optionally substituted aryl; or
R6 and R7 are optionally linked as hereinbefore defined.
Optional substituents on R1, R2, R3, R4, R5, R6 and R7 groups are preferably selected from cyano, and, more preferably from:
halo (e.g. fluoro, chloro or bromo);
C1-6 alkyl, which alkyl group may be linear or branched (e.g. C1-4 allyl (including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl 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 trifluoromethyl); and —OR17;
wherein R17 represents, H or C1-6 alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or t-butyl (which alkyl groups are optionally substituted by one or more halo (e.g. fluoro) groups).
Preferred values of R8 are C1-4 alkyl and, particular, hydrogen.
More preferred compounds include those in which:
R1 represents an aryl group, such as a phenyl group, or a heteroaryl group such as a pyridyl group, both of which groups are optionally substituted by one or two A groups;
R3 and R4 independently represent G1 or, more preferably, H, an aryl group, such as phenyl, or a heteroaryl group such as pyridyl, both of which groups are optionally substituted by one or two A groups;
at least one of R3 and R4 represents optionally substituted aryl or heteroaryl, and up to one other represents G1 or, more preferably, hydrogen;
when R3 or R4 represents an aryl or heteroaryl group, then the other substituents on the essential benzene ring of the compound of formula I (i.e. R2, R5 and R3 or R4 (as appropriate)) independently represent hydrogen or G1 (e.g. halo (such as chloro), cyano, methyl, methoxy, trifluoromethyl or trifluoromethoxy);
R6 represents H or C1-4 alkyl which alkyl group is optionally substituted by one or two G1 groups;
R7 represents C1-4 alkyl which group is optionally substituted by one or two G1 groups, an aryl group, such as a phenyl group, or a heteroaryl group, such as a pyridyl group, which latter two groups are optionally substituted by one or two B groups; or
R6 and R7 are linked to form, together with the nitrogen atom and X group to which they are respectively attached, a 5- to 6-membered ring, optionally containing 1 to 2 heteroatoms;
A represents G1;
G1 represents halo (e.g. chloro) or -A1-R9;
A1 represents a single bond, —OA5- or —N(R10)A4-;
A4 and A5 independently represent a single bond;
B represents G2;
G2 represents halo or -A6-R11;
A6 represents —O—;
R9 represents C1-6 (e.g. C1-3) alkyl, which group is optionally substituted by one or more G3 groups, or an aryl group, such as a phenyl, or a heteroaryl group, such as a pyridyl group;
R10 represents C1-2 alkyl;
R11 represents C1-2 alkyl optionally substituted by one or more G3 groups;
G3 represents halo (especially fluoro);
Especially preferred compounds of the invention are wherein:
R8 represents hydrogen;
R1 represents a phenyl group, substituted, for example in the 3- or, preferably, 4-position by a single -A1-R9 group. In such instances, A1 may represent —OA5-, in which A5 is as hereinbefore defined and is preferably a single bond. R9 may, in such instances, represent C1-5 (e.g. C1-4) alkyl, such as cyclic C3-5 allyl (e.g. cyclopenyl) or, preferably, optionally branched propyl, so forming, for example, a 4-cyclopentoxyphenyl or, more preferably, a 4-isopropoxyphenyl group;
R2 represents halo, cyano, C1-3 alkyl, C1-3 alkoxy (which latter two groups are optionally substituted by one or more halo (e.g. fluoro) groups) or, preferably, H;
R3 represents a phenyl group, substituted, for example in the 3- or, preferably, 4-position by a single -A1-R9 group. In such instances, A1 may represent a single bond or —OA5-. When A represents —OA5-, A5 is as hereinbefore defined and is preferably a single bond aid R9 may represent C1-4 alkyl, such as branched propyl. When A1 represents a single bond, R9 may represent a C1-4 (e.g. C1-2) alkyl group, such as an optionally branched butyl group (e.g. t-butyl) or, more particularly, a methyl group, optionally substituted by one or more G3 groups, in which G3 represents halo (especially fluoro). Thus R1 may represent a 4-tert-butylphenyl or, more particularly, a 4-isopropoxyphenyl or 4-trifluoromethylphenyl group;
R3 may alternatively represent a pyridyl group (e.g. a 2-pyridyl group), optionally substituted, for example in the meta or, preferably, para position relative to the point of attachment of R3 to the indole ring, by a single -A1-R9 group. In such instances, A1 preferably represents a single bond and R9 represents C1-2 alkyl (e.g. methyl) optionally substituted by one or more G3 groups, in which G3 represents fluoro, so forming, for example, a 5-trifluoromethylpyrid-2-yl group;
R4 and R5 independently represent halo, C1-3 alkyl, C1-3 alkoxy (which latter two groups are optionally substituted by one or more halo (e.g. fluoro) groups) or, preferably, H;
R6 may represent H or a C1-3 alkyl group, such as a methyl or n-propyl group, optionally substituted, for example at the terminal position, by a G1 group. In such instances, G1 may represent -A1-R9, in which A1 preferably represents a single bond and R9 preferably represents an aryl group, such as phenyl, or a heteroaryl group, such as pyridyl (especially 3-pyridyl). Thus, R6 may also represent a 3-phenylpropyl, a pyrid-3-ylmethyl or a methyl group;
R7 may represent C1-3 alkyl, such as methyl or n-propyl, optionally substituted, for example, at the terminal position, by a G1 group, an aryl group, such as a phenyl group or a heteroaryl group, such as a pyridyl group, which latter two groups are optionally substituted. For example, the phenyl group may be substituted in the 3- or, preferably, 4-position, by a B group. In the instance wherein the substituent is G1, G1 may represent -A1-R9, in which A1 preferably represents a —N(R10)A4 group, in which A4 preferably represents a single bond, and R10 and R11 are each, independently, C1-2 alkyl, such as methyl. In the instance wherein the substituent is B, B may represent a G2 group, in which G2 is preferably a halo group (such as chloro) or a -A6-R11 group. In such instances, A6 preferably represents —O— and R11 preferably represents C1-2 alkyl, such as methyl, optionally substituted by one or more G3 groups, in which G3 represents halo (especially fluoro). Thus R7 may represent a 3-pyridyl or, more preferably, a dimethylaminopropyl, (4-trifluoromethoxy)phenyl, a 4-chlorophenyl, or a methyl group;
when R6 and R7 are linked together with the nitrogen atom and X group, to which they are respectively attached, then X is —C(O)— or, preferably, a single bond and the ring formed is preferably a 5- to 6-membered ring, optionally containing a further heteroatom (e.g. an oxygen heteroatom) so forming, for example, a pyrrolidinone (e.g. a 1-pyrrolidinone) group or, more preferably, a morpholinyl group (e.g. a 4-morpholinyl group).
Particularly preferred compounds of the invention include those of the example described hereinafter.
Compounds of the invention may be made in accordance with techniques that are well known to those skilled in the art, for example as described hereinafter.
According to a further aspect of the invention there is provided a process for the preparation of a compound of formula I, which process comprises:
(i) reaction of a compound of formula II,
wherein X, R2, R3, R4, R5, R6, R7 and R8 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 Ph3P, 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, xantphos, NaI or an appropriate crown ether such as 18-crown-6-benzene, in the presence of an appropriate base such as NaH, Et3N, pyridine, N,N′-dimethylethylenediamine. Na2CO3, K2CO3, K3PO4, Cs2CO3, t-BuONa or t-BuOK (or a mixture thereof), in a suitable solvent (e.g. dichloromethane, dioxane, toluene, ethanol, isopropanol, dimethylformamide, ethylene glycol, ethylene glycol dimethyl ether, water, dimethylsulfoxide, acetonitrile, dimethylacetamide, N-methylpyrrolidinone, tetrahydrofuran or a mixture thereof) or in the absence of an additional solvent when the reagent may itself act as a solvent (e.g. when R1 represents phenyl and L1 represents bromo, i.e. bromobenzene). 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) reaction of a compound of formula IV,
wherein L1, R1, R2, R3, R4, R5 and R8 are as hereinbefore defined, with a compound of formula V,
HN(R6)XR7 V
wherein X, R6 and R7 are as hereinbefore defined for example under reaction conditions as hereinbefore defined in respect of process step (i);
(iii) reaction of a compound of formula VI,
wherein L3 represents L1 or L2, in which 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 wherein L3 is attached to one or more of the carbon atoms of the benzenoid ring of the indole, and wherein the remaining positions of the benzenoid ring are substituted with 1 to 3 (depending on the number of L3 substituents) R2-R5 substituents, R2-R5 represents any one of the substituents, i.e. R2, R3, R4 and R5, that are already present in that ring (as appropriate), and X, L1, R1, R2, R3, R4, R5, R6, R7 and R8 are as hereinbefore defined, with a compound of formula VII,
R18L4 VII
wherein R18 represents R2, R3, R4 or R5 (as appropriate), and L4 represents L1 (when L3 is L2) or L2 (when L3 is L1) as hereinbefore defined. The skilled person will appreciate that L1 and L2 will be mutually compatible. 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, PdCl2, Pd/C, Pd(OAc)2, Pd(Ph3P)2Cl2, Pd(Ph3P)4, Pd2(dba)3 or NiCl2 and an additive such as t-Bu3P, (C6H1)3P, Ph3P, AsPh3, P(o-Tol)3, 1,2-bis(diphenylphosphino)ethane, 2,2′-bis(di-ter-t-butylphosphino)-1,1′-biphenyl, 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, 1,1′-bis(diphenylphosphinoferrocene), 1,3-bis(diphenyl-phosphino)propane or xantphos, together with a suitable base such as, Na2CO3, K3PO4, Cs2CO3. KOH, NaOH, 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 when L3 or L4 (of the compounds of formulae VI and VII, respectively, represent halo, such compounds may first be activated by:
The skilled person will also appreciate that the magnesium of the Grignard reagent or the lithium of the lithiated species may be exchanged for 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 VI or VII (as appropriate) under conditions known to those skilled in the art, for example such as those described above;
(iv) reaction of a compound of formula VIII,
wherein R1, R2, R3, R4, R5, R6 and R8 are as hereinbefore defined, with a compound of formula IX,
R7XL1 IX
wherein X, R7 and L1 are as hereinbefore defined, for example at around room temperature, below room temperature (e.g. at 0° C.) or above room temperature (e.g. up to 60-70° C.) optionally 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, trifluoromethylbenzene or acetonitrile. This reaction may be performed under an inert atmosphere (e.g. under Ar); or
(v) for compounds of formula I wherein X represents a single bond and R7 is a C1-8 alkyl group, reduction of a compound of formula I, wherein X represents —C(O)— and R7 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, under reaction conditions known to the skilled person.
Compounds of formula II may be prepared by:
Compounds of formula IV may be prepared by:
R1L2 XIII
Compounds of formula VI may be prepared by reaction of a compound of formula XI as hereinbefore defined, with a compound of formula III as hereinbefore defined, for example under reaction conditions such as those described hereinbefore in respect of preparation of compounds of formula I (process step (i)) above.
Compounds of formula VI in which L3 represents L2 may be prepared by reaction of a compound of formula VI 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:
Conversions of the L4 group and the L3 group in the compounds of formulae VII and XI, respectively, may be performed in a similar manner to that described above in respect of converting the L3 group in compounds of formula VI.
Compounds of formula X may be prepared by standard techniques. For example:
Compounds of formula XII may be prepared for example by reaction of a compound of formula X, as hereinbefore defined, with a compound of formula XVIII,
H2NR6 XVIII
wherein R6 is as hereinbefore defined, for example under reaction conditions such as those described hereinbefore in respect of preparation of compounds of formula I (process step (ii)) above;
Compounds of formula XII, wherein R6 represents hydrogen may be prepared for example by an aromatic nitration reaction performed on a compound of formula XV, as hereinbefore defined, followed by reduction of the nitro group to the amino group. Both reactions may be performed under conditions known to the skilled person.
Compounds of formulae III, V, VII, VIII, IX, XI, XIII, XIV, XV, XVI, XVII and XVIII 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.
Indoles of formulae II, IV, VI, VIII, X, XI, XII, XIV, XV, XVI and XVII 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, XI, XII and XV may be prepared by reaction of a compound of formula XIX.
wherein SUB represents the substitution pattern that is present in the compound of formula II, XI, XII or XV to be formed, (G) represents either a —N(R6)C(O)R7 group (as required for formation of compounds of formulae II and XI), a —N(R6)H group (as required for formation of compounds of formula XII) or hydrogen (as required for formation of compounds of formula XV) and R8 is as hereinbefore defined, under Fischer indole synthesis conditions known to the person skilled in the art.
Compounds of formula XV may alternatively be prepared by reaction of a compound of formula XX,
wherein R2, R3, R4 and R5 are as hereinbefore defined with a compound of formula XXI.
N3CH2C(O)OR8 XXI
wherein R8 is as hereinbefore defined, and preferably does not represent hydrogen, under conditions known to the person skilled in the art (i.e. conditions to induce a condensation reaction, followed by a thermally induced cyclisation).
Compounds of formulae XIV and XVII may be prepared by reaction of a compound of formula XXII,
wherein Rx represents a C1-6 alkyl group, Ry represents either R1 as hereinbefore defined (as required for formation of compounds of formula XIV), hydrogen (as required for formation of compounds of formula XVII) or a nitrogen-protected derivative thereof, and R2, R3, R4, R5 and R8 are as hereinbefore defined and, under standard cyclisation conditions known to those skilled in the art.
Compounds of formulae VIII and XII may be prepared by reaction of a compound of formula XXIII,
wherein SUB, R8 and Ry are as hereinbefore defined, for example under intramolecular cyclisation conditions known to those skilled in the art.
Compounds of formula XIX may be prepared by:
Compounds of formulae XX, XXI, XXII, XXIII, XXIV, XXV, XXVI and XXVII are either commercially available, are known in the literature, or may be obtained either by analogy with the processes described herein, or by conventional synthetic procedures, in accordance with standard techniques, from available starting materials using appropriate reagents and reaction conditions. In this respect, the skilled person may refer to inter alia “Comprehensive Organic Synthesis” by B. M. Trost and I. Fleming, Pergamon Press, 1991.
The substituents R1, R2, R3, R4, R5, R6, R7 and R8 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, 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 R8 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 R8 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 R6 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 R6 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 (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 in PGES-1 or a complex of which the mPGES-1 enzyme forms a part, and/or may elicit a in PGES-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 inflammatory bowel disease, irritable bowel syndrome, migraine, headache, low back pain, fibromyalgia, myofascial disorders, viral infections (e.g. hepatitis C and, particularly, influenza, common cold, herpes zoster, and AIDS), bacterial infections, fungal infections, dysmenorrhea, burns, surgical or dental procedures, malignancies (e.g. breast cancer, colon cancer, and prostate cancer), atherosclerosis, gout, arthritis, osteoarthritis, juvenile arthritis, rheumatoid arthritis, fever (e.g. rheumatic fever), ankylosing spondylitis, 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, osteoporosis, asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, allergic disorders, rhinitis, ulcers, coronary heart disease, sarcoidosis and any other disease with an inflammatory component. Other diseases that may be mentioned include inflammatory pain, hyperprostaglandin E syndrome, classic Bartter syndrome, Hodgkin's disease and persistent ductus (PDA).
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 LTC4, FLAP and/or, preferably, a PGES (such as mPGES-1), and/or a method of treatment of a disease in which inhibition of the activity of LTC4, FLAP and/or, preferably, a PGES (and particularly mPGES-1) 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:
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 pairs 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 adminstered 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 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 human mPGES-1 catalyses the reaction where the substrate PGH2 is converted to PGE2. mPGES-1 is expressed in E. coli and the membrane fraction is dissolved in 20 mM NaPi-buffer pH 8.0 and stored at −80° C. In the assay human mPGES-1 is dissolved in 0.1 M 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 UV-detector.
The following is added chronologically to each well:
The invention is illustrated by way of the following examples, in which the following abbreviations may be employed:
Starting materials and chemical reagents specified in the syntheses described below are commercially available from, e.g. Sigma-Aldrich Fine Chemicals.
A mixture of 5-bromoindole-2-carboxylic acid ethyl ester (2 g, 7.5 mmol), 4-isopropoxyphenylboronic acid (2.72 g, 15 mmol), K3PO4 (5.52 g, 26 mmol), Pd(OAc)2 (85 mg, 0.38 mmol), tri-o-tolylphosphine (228 mg, 0.75 mmol), EtOH (20 ml) and toluene (10 mL) was stirred under argon for 20 mm at room temperature, and then heated at 100° C. for 24 h. The mixture was allowed to cool, poured into NaHCO3 (aq., sat.) and extracted with EtOAc. The combined extracts were washed with water and brine and then dried over Na2SO4. Concentration and purification by chromatography gave the sub-title compound (1.81 g, 98%).
A solution of NBS (0.90 g, 5.1 mmol) in acetone (10 mL) was added dropwise to a stirred solution of 5-(4-isopropoxyphenyl)indole-2-carboxylic acid ethyl ester (1.5 g, 4.62 mmol; see step (a)) in acetone (35 mL) at room temperature. After 2.5 h, additional NBS (164 mg, 0.92 mmol) was added and the temperature was raised to 45° C. and the mixture was stirred at that temperature for 1.5 h. The mixture was allowed to cool, poured into Na2S2O3 (aq. 10%), and extracted with EtOAc. The combined extracts were washed with Na2S2O3 (aq. 10%), NaHCO3 (aq. sat), brine and dried over Na2SO4. The solvents were evaporated under reduced pressure and the residue crystallised from ethanol to yield the sub-title compound (1.63 g, 88%).
A mixture of 3-bromo-5-(4-isopropoxyphenyl)indole-2-carboxylic acid ethyl ester, ethyl ester (700 mg, 1.74 mmol; see step (b)), Cu(OAc)2 (632 mg, 3.48 mmol), Et3N (489 μL, 3.48 mmol), pyridine (284 μL, 3.48 mmol), 4-isopropoxyphenylboronic acid (626 mg, 3.48 mmol) and 3 Å molecular sieves in dichloroethane was stirred vigorously at ambient temperature for 30 h. The mixture was filtered through Celite®, the filter cake washed with EtOAc and the solvents concentrated. The residue was purified by chromatography to give the sub-title compound (831 mg, 89%).
3-Bromo-1,5-bis(4-isopropoxyphenyl)indole-2-carboxylic acid ethyl ester (230 mg, 0.43 mmol) in dioxane (3 mL), followed by N,N′-dimethylethylenediamine (14 μL, 12 mg, 0.13 mmol) were added whilst stirring to acetamide (76 mg, 1.29 mmol), CuI (8 mg, 0.04 mmol) and K3PO4 (191 mg, 0.90 mmol) in a pressure tube under argon at room temperature. The septum inlet was replaced with a teflon screw-cap and the mixture was heated at 100° C. for 16 hours. The mixture was subsequently cooled and then filtered through Celite® and the filter cake washed with EtOAc. The combined filtrates were concentrated and purified by chromatography to afford the title compound (149 mg, 67%).
A mixture of 3-acetamido-1,5-bis(4-isopropoxyphenyl)indole-2-carboxylic acid ethyl ester (129 mg, 0.250 mmol; see step (d)), aqueous NaOH (1 M, 2 mL) and MeCN (2 mL) was heated under microwave irradiation at 120° C. for 1.5 h, allowed to cool, then acidified with HCl (aq., 1M) to pH 2 and extracted with EtOAc. The combined extracts were washed with water, brine and dried over Na2SO4. Concentration, purification by chromatography, and recrystallisation from ethyl acetate and hexanes gave the title compound.
200 MHz 1H-NMR (DMSO-d6, ppm) δ 13.1-12.7 (1H, br s), 9.78 (1H, s), 7.85-7.80 (1H, m), 7.58-7.48 (3H, m), 7.29-7.20 (2H, m), 7.08-6.96 (5H, m), 4.68 (1H, septet, J=6.0 Hz), 4.64 (1H, septet, J=6.0 Hz), 2.15 (3H, s), 1.33 (6H, d, J=6.0 Hz), 1.28 (6H, d, J=6.0 Hz).
The title compound was prepared in accordance with Example 1 using 4-(dimethylamino)butyric acid amide in Example 1(d) instead of acetamide.
200 MHz 1H-NMR (DMSO-d6/CF3COOD, ppm) δ 9.9 (1H, s), 9.6-9.4 (1H, br s), 7.81 (1H, s), 7.59-7.49 (3H, m), 7.29-7.20 (2H, m), 7.10-6.96 (5H, m), 4.68 (1H, septet. J=6.0 Hz), 4.65 (1H, septet, J=6.0 Hz), 3.23-3.07 (2H, m), 2.82 (3H, s), 2.80 (3H, s), 2.62-2.52 (2H, m), 1.33 (6H, d, J=6.0 Hz), 1.28 (6H, d, J=6.0 Hz).
A mixture of 3-bromo-1,5-bis(4-isopropoxyphenyl)indole-2-carboxylic acid ethyl ester (200 mg, 0.37 mmol; see Example 1 (c)), methanesulfonamide (71 mg, 0.74 mmol), Pd2(dba)3 (17 mg, 0.019 mmol), xantphos (33 mg, 0.057 mmol), Cs2CO3 (181 mg, 0.56 mmol) and dioxane (3 ml) was heated under argon at 110° C. for 20 h, and then allowed to cool to room temperature. Water was added and the mixture was extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4, and concentrated. Purification by chromatography yielded the sub-title compound (120 mg, 59%).
The title compound was prepared by hydrolysis of 1,5-bis(4-isopropoxyphenyl)-3-(methylsulfonamido)indole-2-carboxylic acid ethyl ester (see step (a) above) in accordance with the procedure described in Example 1(e).
200 MHz 1H-NMR (DMSO-d6, ppm) δ 13.5-13.0 (1H, br s), 9.21 (1H, s), 7.97 (1H, d, J=1.2 Hz), 7.61-7.47 (3H, m), 7.36-7.26 (2H, m), 7.11-6.96 (5H, m), 4.69 (1H, septet, J=6.0 Hz), 4.65 (1H, septet, J=6.0 Hz), 3.02 (3H, s), 1.33 (6H, d, J=6.0 Hz), 1.29 (6H, d, J=6.0 Hz).
A mixture of 3-bromo-1,5-bis(4-isopropoxyphenyl)indole-2-carboxylic acid ethyl ester (210 mg, 0.39 mmol; see Example 1(c)), 3-phenyl-1-propylamine (67 μL, 63 mg, 0.47 mmol), Pd2(dba)3 (12.5 mg, 0.014 mmol), BINAP (37 mg, 0.052 mmol) and Cs2CO3 (178 mg, 0.54 mmol) in toluene (2 mL) was heated under argon at 120° C. for 16 h. Water was added and the mixture was extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4, and concentrated. Purification by chromatography yielded the title compound.
4-(Trifluoromethoxy)benzoyl chloride (61 μL, 87 mg, 0.385 mmol) was added to a solution of 1,5-bis(4-isopropoxyphenyl)-3-(3-phenylpropylamino)indole-2-carboxylic acid ethyl ester (200 mg, 0.34 mmol; see step (a)) in toluene (3 mL) at room temperature. The reaction mixture was heated under argon at 80° C. for 50 min and then allowed to cool. NaHCO3 (aq. sat., 30 mL) was added and the mixture stirred for 40 min, after which it was extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4, and concentrated. Purification by chromatography yielded the sub-title compound.
The title compound was prepared by hydrolysis of 1,5-bis(4-isopropoxyphenyl)-3-(N-(3-phenylpropyl)-4-(trifluoromethoxy)benzamido)-indole-2-carboxylic acid ethyl ester (see step (b)) in accordance with the procedure described in Example 1(e).
200 MHz 1H-NMR (DMSO-d6, ppm) δ 7.77-7.31 (6H, m), 7.26-6.85 (14H, m), 4.73-4.53 (2H, m), 4.14-3.69 (2H, m), 2.71-2.54 (2H, m), 1.99-1.77 (2H, m), 1.36-1.20 (12H, m).
The title compound was prepared in accordance with the procedures described in Example 4 using pyrid-3-ylmethanamine and acetyl chloride instead of 3-phenyl-1-propylamine and 4-(trifluoromethoxy)benzoyl chloride.
200 MHz 1H-NMR (DMSO-d6, ppm) δ 8.53-8.36 (2H, m), 7.73 (1H, d, J=7.6 Hz), 7.42-7.20 (6H, m), 7.10-6.88 (6H, m), 5.36 (1H, d, J=14.1 Hz), 4.65 (1H, septet, J=6.1 Hz), 4.62 (1H, septet, J=6.0 Hz), 4.50 (1H, d, J=14.1 Hz), 1.85 (3H, s), 1.31 (6H, d, J=6.1 Hz) 1.26 (6H, d, J=6.0 Hz).
The reaction was performed with the exclusion of light. NaI (2.04 g, 13.6 mmol) was added portion-wise whilst stirring to N-chlorosuccinimide (1.83 g, 13.6 mmol) in acetone (125 mL), followed by 5-(4-(trifluoromethyl)phenyl)indole-2-carboxylic acid ethyl ester (3.8 g, 11.4 mmol; which compound was prepared in accordance with the procedure described in Example 1 (a) using 4-trifluoromethylphenyl boronic acid instead of 4-isopropoxyphenyl boronic acid), in acetone (60 mL) at room temperature. After 2 h the mixture was poured into Na2S2O3 (aq. 10%) and extracted with EtOAc. The combined extracts were washed with NaHCO3 (sat. aq.), brine, and dried over Na2SO4. The solvents were removed under reduced pressure and the residue triturated with petroleum ether to yield the title compound (4.9 g 94%) that was used in the next step without further purification.
The title compound was prepared in accordance with the procedures described in Example 1 (c) to 1 (e), using 4-chlorobenzamide instead of acetamide.
200 MHz 1H-NMR (DMSO-d6, ppm) δ 11.2-10.8 (1H, br s), 8.27 (1H, s), 8.13-8.03 (2H, m), 7.93-7.73 (4H, m), 7.68-7.58 (3H, m), 7.31-7.21 (2H, m), 7.11 (1H, d, J=9.0 Hz), 7.09-6.99 (2H, m), 4.66 (1H, septet, J=6.1 Hz), 1.32 (6H, d, J=6.0 Hz).
The sub-title compound was prepared in accordance with the procedure described in Example 1 (a) using 5-bromoindole-2-carboxylic acid ethyl ester and 4-trifluoromethylphenylboronic acid instead of 4-isopropoxyphenylboronic acid.
The sub-title compound was prepared in accordance with the procedure described in Example 1(b) and 1(c) from 5-(4-(trifluoro-methyl)phenyl)indole-2-carboxylic acid ethyl ester (see step (a)), NBS and 4-isopropoxyphenylboronic acid.
Morpholine (34.5 μL, 0.4 mmol), followed by anhydrous toluene (10 mL) was added under argon to a mixture of Pd2(dba)3 (6 mg, 0.0066 mmol), BINAP (6.12 mg, 0.0099 mmol), Cs2CO3 (150 mg, 0.46 mmol) and 3-bromo-1-(4-isopropoxyphenyl)-5-(4-(trifluoromethyl)phenyl)indole-2-carboxylic acid ethyl ester (180 mg, 0.33 mmol; see step (b)). The mixture was stirred at 100° C. for 24 h, after which an additional portion of BINAP (2.1 mg, 0.0033 mmol) was added. The heating was continued for 24 h after which additional portions of Pd2(dba)3 (3.02 mg, 0.0033 mmol) and BINAP (3.06 mg, 0.005 mmol) were added. The mixture was heated for a further 12 h, allowed to cool, diluted with Et2O, and filtered through Celite®. The filtrate was concentrated and the residue purified by chromatography to afford the sub-title compound (116 mg, 64%).
The title compound was prepared by hydrolysis of 1-(4-isopropoxyphenyl)-3-(4-morpholino)-5-(4-(trifluoromethyl)phenyl)indole-2-carboxylic acid ethyl ester (see step (c)) in accordance with the procedure described in Example 1(e).
200 MHz 1H-NMR (DMSO-d6, ppm) δ 8.27 (1H, d, J=1.4 Hz), 8.02-7.94 (2H, m), 7.85-7.76 (2H, m), 7.67 (1H, dd, J=1.4, 8.8 Hz), 7.31-7.22 (2H, m), 7.16 (1H, d, J=8.8 Hz), 7.07-6.99 (2H, m), 4.68 (1H, septet, J=6.0 Hz), 3.91-3.76 (4H, m), 3.50-3.38 (4H, m), 1.32 (6H, d, J=6.0).
Cu(NO3)2 was added to acetic anhydride (10 mL) at −5° C. (whilst stirring the mixture). After 10 min, a solution of 5-bromo-1H-indole-2-carboxylic acid ethyl ester (2.0 g, 7.46 mmol) in acetic anhydride (25 mL) was added portion-wise. The mixture was stirred for 2 h at −5° C., solid was removed by filtration and washed with acetic anhydride. The filtrate was poured into ice-water (150 mL) and stirred for 5 h. The precipitate was filtered, washed with water and dried to afford the sub-title compound (2.2 g, 94%).
The sub-title compound was prepared from 5-bromo-3-nitro-1H-indole-2-carboxylic acid ethyl ester (see step (a) above) in accordance with the procedure described in Example 1(c).
The sub-title compound was prepared in accordance with the procedure described in Example 1(a) using 5-bromo-1-(4-isopropoxyphenyl)-3-intro-1H-indole-2-carboxylic acid ethyl ester (see step (b) above) and 4-tert-butylphenylboronic acid instead of 4-isopropoxyphenylboronic acid.
Pd—C (550 mg of 10%) was added to the solution of 5-(4-tert-butylphenyl)-1-(4-isopropoxyphenyl)-3-intro-1H-indole-2-carboxylic acid ethyl ester (1.1 g, 2.20 mmol; see step (c) above) in EtOAc (50 mL) and the mixture was stirred for 10 h under hydrogen (1 atm). After filtration through Celite®, the filtrate was concentrated and the residue purified by chromatography to afford the sub-title compound (760 mg, 73%).
A solution of 3-amino-5-(4-tert-butylphenyl)-1-(4-isopropoxyphenyl)-1H-indole-2-carboxylic acid ethyl ester (300 mg, 0.64 mmol; see step (d) above) in DMF (3 mL) was added to a stirred suspension of NaH (23 mg, 0.70 mmol) in DMF (1 μL) at 0° C. After stirring at 0° C. for 30 min, a solution of methyl iodide (60 mL, 0.96 mmol) in DMF (1 mL) was added portion-wise. The reaction was left to stir at room temperature for 14 h, then poured into water and extracted with EtOAc. The combined organic extracts were washed with water, brine and dried (Na2SO4). Removal of the solvent and purification by chromatography afforded the sub-title compound (200 mg, 64%).
A mixture of 5-(4-tert-butylphenyl)-1-(4-isopropoxyphenyl)-3-methylamino-1H-indole-2-carboxylic acid ethyl ester (200 mg, 0.41 mmol; see step (d) above), acetyl chloride (59 μL. 0.82 mmol), triethylamine (115 μL, 0.82 mmol) and dry MeCN (5 mL) was stirred at room temperature under argon for 1.5 h. The mixture was poured into HCl (1N) and extracted with EtOAc. The combined organic extracts were washed with water, brine and dried (Na2SO4). Removal of the solvent and purification by chromatography yielded the sub-title compound (87 mg, 40%).
The title compound was prepared by hydrolysis of 3-(acetylmethylamino)-5-(4-tert-butylphenyl)-1-(4-isopropoxyphenyl)-1H-indole-2-carboxylic acid ethyl ester (see step (f) above) in accordance with the procedure described in Example 1(e).
200 MHz 1H-NMR (acetone-d6, ppm) δ 7.91-7.89 (1H, m) 7.72-7.64 (3H, m) 7.55-7.48 (2H, m) 7.41-7.32 (2H, m) 7.22 (1H, dd, J=8.8, 0.7 Hz) 7.13-7.05 (2H, m) 4.73 (1H, septet, J=6.0 Hz) 3.33 (3H, s) 1.89 (3H, s) 1.38 (6H, d, J=6.0 Hz) 1.36 (9H, s).
Pd2(dba)3 (275 mg, 0.30 mmol) and tricyclohexylphosphine (504 mg, 1.80 mmol) in dioxane (30 mL) were added under argon to a stirred mixture of 5-bromo-1H-indole-2-carboxylic acid ethyl ester (6.0 g, 22.4 mmol), KOAc (3.3 g, 33.6 mmol), bis(pinacolato)diboron (6.3 g, 24.6 mmol) and dioxane (20 mL) at 80° C. The resulting mixture was stirred at 80° C. for 3 h, cooled to room temperature and filtered through a Celite® pad. The filter cake was washed with EtOAc and the combined filtrates were concentrated and purified by chromatography to yield the sub-title compound (6.8 g, 97%).
A stirred mixture of 5-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-indole-2-carboxylic acid ethyl ester (3.00 g, 9.52 mmol; see step (a) above), 2-bromo-5-(trifluoromethyl)pyridine (3.23 g, 14.28 mmol), sodium carbonate (2M, 14.30 mL, 28.56 mmol), Pd(PPh3)4 (540 mg, 0.50 mmol), EtOH (10 mL) and toluene (40 mL) were heated at 80° C. for 24 h. The mixture was cooled to room temperature, poured into water and extracted with EtOAc. The combined extracts were washed with water, brine and dried (Na2SO4). Solvent removal and purification by chromatography gave the sub-title compound (3.0 g, 94%).
The sub-title compound was prepared in accordance with the procedure described in Example 6(a) using 5-(5-trifluoromethylpyrid-2-yl)-1H-indole-2-carboxylic acid ethyl ester (see step (b) above).
The sub-title compound was prepared in accordance with the procedure described in Example 1(c) using 3-iodo-5-(5-trifluoromethylpyrid-2-yl)-1H-indole-2-carboxylic acid ethyl ester (see step (c) above) and 4-cyclopentoxyphenylboronic acid instead of 4-isopropoxyphenylboronic acid.
The sub-title compound was prepared in accordance with the procedure described in Example 1(d) using 1-(4-cyclopentoxyphenyl)-3-iodo-5-(5-trifluoromethylpyrid-2-yl)-1H-indole-2-carboxylic acid ethyl ester (see step (d) above) and 4-dimethylaminobutyramide instead of acetamide.
The title compound was prepared by hydrolysis of 1-(4-cyclopentoxy-phenyl)-3-(4-dimethylaminobutyrylamino)-5-(5-trifluoromethylpyrid-2-yl)-1H-indole-2-carboxylic acid ethyl ester (see step (e)) in accordance with the procedure described in Example 1(e).
200 MHz 1H-NMR (DMSO-d6, ppm) δ 11.5-10.5 (1H, br s) 9.03-8.97 (1H, m) 8.91-8.86 (1H, m) 8.28-8.19 (1H, m) 8.08 (1H, d, J=8.2 Hz) 8.01-7.93 (1H, m) 7.23-7.12 (2H, m) 7.04 (1H, d, J=9.0 Hz) 7.01-6.92 (2H, m) 4.90-4.78 (1H, m) 3.02-2.90 (2H, m) 2.91 (6H, s) 2.58-2.50 (2H, m, overlapped with DMSO) 2.09-1.53 (10H, m).
The sub-title compound was prepared in accordance with the procedure described in Example 1(d) using 1-(4-cyclopentoxyphenyl)-3-iodo-5-(5-trifluoromethylpyrid-2-yl)-1H-indole-2-carboxylic acid ethyl ester (see Example 9(d)) and pyrrolidin-2-one instead of acetamide.
The title compound was prepared by hydrolysis of 1-(4-cyclopentoxy-phenyl)-3-(2-oxopyrrolidin-1-yl)-5-(5-trifluoromethylpyrid-2-yl)-1H-indole-2-carboxylic acid ethyl ester (see step (a) above) in accordance with the procedure described in Example 1(e).
200 MHz 1H-NMR (DMSO-d6, ppm) δ 13.13 (1H, s) 9.05-9.01 (1H, m) 8.42-8.39 (1H, m) 8.33-8.22 (2H, m) 8.16 (1H, dd, J=8.9, 1.6 Hz) 7.36-7.27 (2H, m) 7.19 (1H, d, J=8.9 Hz) 7.10-7.01 (2H, m) 4.95-4.85 (1H, m) 3.95-3.83 (2H, m) 2.50-2.43 (2H, m, overlapped with DMSO) 2.33-2.14 (2H, m) 2.07-1.87 (2H, m) 1.87-1.55 (6H, m).
The sub-title compound was prepared in accordance with the procedure described in Example 1 (c) using 3-iodo-5-(5-trifluoromethylpyridin-2-yl)-1H-indole-2-carboxylic acid ethyl ester (see Example 9 (c)) and 4-isopropoxyphenylboronic acid.
The sub-title compound was prepared in accordance with the procedure described in Example 1 (d) using 3-iodo-1-(4-isopropoxyphenyl)-5-(5-trifluoromethylpyridin-2-yl)-1H-indole-2-carboxylic acid ethyl ester (see step (a) above) and acetamide.
The title compound was prepared by hydrolysis of 3-acetylamino-1-(4-isopropoxyphenyl)-5-(5-trifluoromethylpyridin-2-yl)-1H-indole-2-carboxylic acid ethyl ester (see step (b) above) in accordance with the procedure described in Example 1 (e).
200 MHz 1H-NMR (DMSO-d6, ppm) δ 13.1-13.0 (1H, br s) 9.86 (1H, s) 9.05-9.00 (1H, m) 8.51 (1H, d, J=1.4 Hz) 8.30-8.23 (1H, m) 8.17 (1H, d, J=8.6 Hz) 8.10 (1H, dd, J=8.8, 1.4 Hz) 7.33-7.23 (2H, m) 7.13 (1H, d, J=8.8 Hz) 7.09-7.02 (2H, m) 4.69 (1H, septet, J=6.0 Hz) 2.17 (3H, s) 1.33 (6H, d, J=6.0 Hz).
A solution of 3-acetylamino-1-(4-isopropoxyphenyl)-5-(5-trifluoromethyl-pyridin-2-yl)-1H-indole-2-carboxylic acid ethyl ester (196 mg, 0.37 mmol; see Example 11 (b)) in DMF (4 mL) was added to a stirred suspension of NaH (13 mg, 0.41 mmol) in DMF (2 mL) at 0° C. After stirring at 0° C. for 30 min, a solution of methyl iodide (49 μL, 0.78 mmol) in DMF (2 mL) was added portion-wise. The reaction was left to stir at room temperature for 14 h, then poured into water and extracted with EtOAc. The combined extracts were washed with water, brine and dried over Na2SO4. The organic phase was concentrated and the product purified by chromatography to give the sub-title compound (169 mg, 84%).
The title compound was prepared by hydrolysis of 3-(acetylmethylamino)-1-(4-isopropoxyphenyl)-5-(5-trifluoromethylpyridin-2-yl)-1H-indole-2-carboxylic acid ethyl ester (see step (a) above) in accordance with the procedure described in Example 1 (e).
200 MHz 1H-NMR (DMSO-d6, ppm) δ 13.6-12.9 (1H, br s) 9.06-9.00 (1H, m) 8.48-8.44 (1H, m) 8.35 (1H, d, J=8.6 Hz) 8.29-8.21 (1H, m) 8.20 (1H, dd, J=8.8, 1.4 Hz) 7.40-7.31 (2H, m) 7.22 (1H, d, J=8.8 Hz) 7.11-7.02 (2H, m) 4.71 (1H, septet, J=6.0 Hz) 3.24 (3H, s) 1.82 (3H, s) 1.34 (6H, d, J=6.0 Hz).
1-(4-Isopropoxyphenyl)-3-nicotinamide-5-(5-trifluoromethylpyridin-2-yl)-1H-indole-2-carboxylic acid was prepared in accordance with the procedures described herein.
Title compounds of the examples were tested in the biological test described above and were found to exhibit 50% inhibition of mPGES-1 at a concentration of 10 μM or below. For example, for the following compounds of the examples, 50% inhibition was obsessed at:
Example 13: 190 nM
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/GB05/02396 | 6/17/2005 | WO | 00 | 11/20/2007 |
| Number | Date | Country | |
|---|---|---|---|
| 60580402 | Jun 2004 | US |
