Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
  • A61K31/404—Indoles, e.g. pindolol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
  • A61P11/06—Antiasthmatics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/12—Drugs for disorders of the urinary system of the kidneys
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/06—Antipsoriatics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
  • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/06—Antimigraine agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P27/00—Drugs for disorders of the senses
  • A61P27/02—Ophthalmic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/10—Antimycotics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/08—Antiallergic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/04—Indoles; Hydrogenated indoles
  • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
  • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

• This invention relates to novel pha ⁇ naceutically -useful compounds, which compounds are useful as mhibitors of enzymes belonging to the membrane- associated proteins in the eicosanoid and glutathione metabolism (MAPEG) family.
• MAPEG membrane-associated proteins in the eicosanoid and glutathione metabolism
• Members of the MAPEG family include the microsomal prostaglandin E synthase-1 (mPGES-1), 5-lipoxygenase-activating protein (FLAP), leukotriene C synthase and microsomal glutathione S-transferases (MGSTL MGST2 and MGST3).
• the compounds are of potential utility in the treatment of inflammatory diseases including respiratory diseases.
• the mvention also relates to the use of such compounds as medicaments, to pharmaceutical compositions contaming them, and to synthetic routes for their production
• Inflammatory diseases that affect the population include asthma, inflammatory bowel disease, rheumatoid arthritis, osteoarthritis, rhinitis, conjunctivitis and dermatitis.
• Inflammation is also a common cause of pain. Inflammatory pain may arise for numerous reasons, such as infection, surgery or other trauma. Moreover, several diseases including malignancies and cardioavascular diseases are known to have inflammatory components adding to the symptomatology of the patients.
• Asthma is a disease of the airways that contains elements of both inflammation and bronchoconstriction. Treatment regimens for asthma are based on the severity of the condition. Mild cases are either untreated or are only treated with inhaled ⁇ -agonists which affect the bronchoconstriction element, whereas patients with more severe asthma typically are treated regularly with inhaled corticosteroids which to a large extent are anti- inflammatory in their nature.
• COPD chronic obstructive pulmonary disease
• COX cyclooxygenase
• COXs metabolise arachidonic acid to the unstable intermediate prostaglandin H 2 (PGH 2 ).
• PGH 2 is further metabolised to other prostaglandins including PGE 2 , PGF 2 ⁇ , PGD 2 , prostacyclin and thromboxane A 2 .
• PGE 2 metabolise arachidonic acid to the unstable intermediate prostaglandin H 2
• PGD 2 metabolised to other prostaglandins
• PGE 2 , PGF 2 ⁇ , PGD 2 prostacyclin and thromboxane A 2 .
• These arachidonic acid metabolites are known to have pronounced physiological and pathophysiological activity mcluding pro- inflammatory effects.
• PGE 2 in particular is known to be a strong pro-inflammatory mediator, and is also known to induce fever and pain. Consequently, numerous drugs have been developed with a view to inhibiting the formation of PGE 2 , including "NSAIDs” (non-steroidal antiinflammatory drugs) and “coxibs” (selective COX-2 inhibitors). These drugs act predominantly by inhibition of COX- 1 and/or COX-2, thereby reducing the formation of PGE 2 .
• NSAIDs non-steroidal antiinflammatory drugs
• coxibs selective COX-2 inhibitors
• 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.
• drugs which act by ihibition of COXs are therefore known/suspected to cause adverse biological effects.
• the non-selective inhibition of COXs by NSAIDs may give rise to gastrointestinal side-effects and affect platelet and renal function.
• PGH 2 may be transformed to PGE 2 by prostaglandin E synthases (PGES).
• PGES prostaglandin E synthases
• mPGES-1 and mPGES-2 microsomal prostaglandin E synthases
• cPGES cytosolic prostaglandin E synthase
• the leukotrienes (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- contaming leukotrienes C , D 4 and E 4 (CysLTs) are mainly very potent bronchoconstrictors and have thus been implicated in the pathobiology of asthma.
• CysLT The biological activities of the CysLTs are mediated through two receptors designated CysLT] and CysLT 2 .
• LTRas leukotriene receptor antagonists
• These drugs may be given orally, but do not control inflammation satisfactorily.
• the presently used LTRas are higlily selective for CysLT]. 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.
• 5-lipoxygenase 5-lipoxygenase-activating protein (FLAP), and leukotriene C 4 synthase may be mentioned.
• FLAP inhibitor would also decrease the fonnation of the proinflammatory LTB 4 .
• mPGES-1, FLAP and leukotriene C 4 synthase belong to the membrane- associated proteins in the eicosanoid and glutathione metabolism (MAPEG) family.
• Other members of this family include the microsomal glutathione S-transferases (MGST1, MGST2 and MGST3).
• MGST1, MGST2 and MGST3 microsomal glutathione S-transferases
• agents that are capable of inhibiting the action of mPGES- 1, and thus reducing the formation of the specific arachidonic acid metabolite PGE are likely to be of benefit in the treatment of inflammation.
• 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.
• X represents a single bond, -C(O)- or -S(0) -;
• R 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 R 2 , R J , R 4 and R D 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, G 1 .
• R 6 , R 7 and R 8 independently represent, on each occasion when used above:
• R 6 and R 7 may be linked together to form along with the N atom and
• X group to which R are respectively attached a 3- to 8-membered ring, optionally containing 1 to 3 heteroatoms and/or 1 to 3 double bonds, wliich ring is optionally substituted by one or more substituents selected from G 1 and/or Z 1 ;
• A represents, on each occasion when mentioned above: I) an aryl group or a heteroaryl group, both of wliich are optionally substituted by one or more substituents selected from B; II) Cj.g alkyl or a heterocycloalkyl group, both of which are optionally substituted by one or more substituents selected from G and/or Z 1 ;
• 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) hetereoatoms and or 1 to 2 (e.g. 1) double bonds, and which is optionally substituted by halo or C ]-s alkyl, which latter group is optionally substituted by halo;
• G 1 represents, on each occasion when mentioned above, halo, cyano, -N 3 , -N0 2 , -ONO. or -A ⁇ R 9 ; wherein A 1 represents a single bond or a spacer group selected from -C(0)A 2 -, -S(0) n A 3 -, -N(R 10 )A 4 - or -OA 5 -, in which: A 2 and A 3 mdependently represent a single bond.
• a 4 and A 5 independently represent a single bond, -C(O)-, -C(0)N(R 10 )-, -C(0)0-, -S(0) n - or -S(0) n N(R 10 )-;
• 0 G " represents, on each occasion when mentioned above, halo, cyano, -N 3 , -N0 2> -ON0 2 or -A 6 -R ⁇ ; wherein A 6 represents a single bond or a spacer group selected from -C(0)A 7 - ; -S(0) n A 8 -, -N(R 12 )A 9 - or -OA 10 -, in which:
• a 7 and A 8 independently represent a single bond, -0-, -N(R 12 )- or -C(O)-;
• a 9 and A 10 independently represent a single bond, -C(O)-, -C(0)N(R 12 )-, -C(0)0-, -S(0) n - or -S(0) n N(R 12 )-;
• R 10 , R n and R 1" are mdependently selected from: i) hydrogen; ii) an aryl group or a heteroaryl group, both of which are optionally substituted by one or more substituents selected from G , methylenedioxy, difluoromethylenedioxy and or dimethylmethylenedioxy; iii) C].g alkyl or a heterocycloalkyl group, both of which are optionally substituted by G and/or Z ; or any pair of R 9 and R 10 , or R 1 1 and R 12 , 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 G and/or Z ;
• G 3 represents, on each occasion when mentioned above, halo, cyano, -N 3 ,
• a 11 represents a single bond or a spacer group selected from
• a 12 and A 13 independently represent a single bond, -0-, -N(R 14 )- or -C(O)-;
• a 14 and A 15 mdependently represent a single bond, -C(O)-, -C(0)N(R 14 )-, -C(0)0-, -S(0) justify- or -S(0) n N(R 14 )-;
• n represents, on each occasion when mentioned above, 1 or 2;
• R 13 and R 14 may, for example when present on the same or on adjacent atoms, be linked together to form with those, or other relevant, atoms a further 3- to 8-membered ring, optionally containing 1 to 3 heteroatoms and/or 1 to 3 double bonds, which ring is optionally substituted by one or more substituents selected from halo, C 1 - alkyl, -N(R 1:, )(R 16 ),
• R 15 and R 16 are mdependently selected from hydrogen and C 1-4 alkyl, which latter group is optionally substituted by one or more halo groups;
• phrases and salts are refe ⁇ -ed to hereinafter as "the compounds of the invention".
• phrases of the invention include acid addition salts and base addition salts.
• Such salts may be fo ⁇ ned 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 mvention 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 (entadel) and Z (zusammen) geometric isomers about each individual double bond. All such isomers and mixtures thereof are included within the scope of the invention.
• Compounds of the invention may also contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereoisomerism.
• Diastereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation.
• the various stereoisomers may be isolated by separation of a racemic or other mixture of the compounds using conventional, e.g. fractional crystallisation or HPLC, techniques.
• the desired optical isomers may be made by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation or epimerisation (i.e.
• a 'chiral poof method by reaction of the appropriate starting material with a 'chiral auxiliary' which can subsequently be removed at a suitable stage, by derivatisation (i.e. a resolution, including a dynamic resolution), for example with a homochiral acid followed by separation of the diastereomeric derivatives by conventional means such as chromatography. or by reaction with an appropriate chiral reagent or chiral catalyst all under conditions "known to the skilled person. All stereoisomers and mixtures thereof are included within the scope of the invention.
• C 1 -q alkyl 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 C 3-q cycloalkyl group).
• C 3-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 (fo ⁇ ning, for example, a C 3-q cycloalkenyl, a C 8 cycloalkynyl or, more particularly, a C 2-q alkenyl or a C 2-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, fo ⁇ ning a so-called "spiro"-compound.
• halo when used herein, includes fluoro, chloro, bromo and iodo.
• Heterocycloalkyl groups that may be mentioned include those in wliich at least one (e.g. one to four) of the atoms in the ring system is other than carbon (i.e. a heteroatom), and i wliich the total number of atoms in the ring system is between three and twelve (e.g. between five and ten). Further, such heterocycloalkyl groups may be saturated or unsaturated containing one or more double and/or triple bonds, forming for example a C 2-q (e.g. C 3-q ) heterocycloalkenyl (where q is the upper limit of the range) or a C 3-q heterocycloalkynyl group.
• a C 2-q e.g. C 3-q
• heterocycloalkenyl where q is the upper limit of the range
• C 3-q heterocycloalkynyl group e.g. C 3-q
• C 2-q heterocycloalkyl groups that may be mentioned include aziridinyl, azetidinyl, dihydropyranyl.
• dihydropyridyl dihydropyrrolyl (including 2,5-dihydropyrrolyl), dioxolanyl (including 1,3- dioxolanyl), dioxanyl (mcluding L3-dioxanyl and 1,4-dioxanyl), dithianyl (including 1.4-dithianyl), dithiolanyl (including 1,3-dithiolanyl), imidazolidinyl, imidazolhtyl, morpholinyl.
• oxetanyl oxhanyl, piperazinyl, piperidinyl, pyranyl, pyrazolidinyl, pyrrolidinonyl, pyrrolidinyl, pyrrolmyl, quinuclidinyl, sulfolanyl, 3-sulfolenyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydropyridyl, thietanyl, thiiranyl, thiolanyl, thiomorpholinyl, trithianyl (including 1,3,5-trithianyl). tropanyl and the like.
• heterocycloalkyl groups that may be mentioned include 7-azabicyclo[2.2.3 ]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 includmg a heteroatom.
• 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
• heterocycloalkyl groups may also be in the vV- or S- oxidised form.
• bicyclic when employed in the context of cycloalkyl and heterocycloalkyl groups refers to such groups in which the second ring is fonned between two adjacent atoms of the first rmg.
• 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 alkyl ene or heteroalkylene chain (as appropriate).
• Aryl groups that may be mentioned include C 6-]3 (e.g. C 6 -]o) 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.
• C 6- i 3 aryl groups include phenyl, naphthyl and the like, such as fluorenyl and, more particularly, 1,2,3,4-tetrahydronaphtliyl, 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 (includmg 1,3-benzodioxolyl), benzofuranyl, benzofurazanyl.
• benzothiazolyl (mcluding 2,1 ,3-benzothiazolyl), benzoxadiazolyl (including 2,1,3- benzoxadiazolyl), benzoxazinyl (including 3.4-dihydro-2H-l,4- benzoxazinyl), benzoxazolyl, benzimidazolyl, beiizomorpholinyl, benzoselenadiazolyl (including 2,1 ,3-benzoselenadiazotyl), benzothienyl, carbazolyl, chromanyl, cinnolinyl, furanyl, imidazolyl, irnidazo[l,2- tfjpyridyl, indazolyl, indolinyl, indolyl, isobenzofuranyl, isochromanyl, isoindolinyl.
• pteridinyl purinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl. quinolinyl, quinolizinyl, quinoxalinyl. tetrahydroiso- quinolinyl (including 1,2,3,4-tetrahydroisoquinolinyl and 5,6,7,8- tetrahydroisoquinolinyl).
• tetrahydroqumolinyl including 1 ,2,3,4- tetrahydroquinolinyl and 5,6,7,8-tetrahydroquinolinyl
• tetrazolyl including 1,2,3-thiadiazolyl, 1,2.4-thiadiazolyl and 1,3,4-thiadiazolyl
• thiazolyl 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 includmg a heteroatom.
• 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.
• heteroaiyl 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.
• optionally substituted methylenedioxy groups when attached to a ring system, are fonned between any two adjacent atoms of the ring system.
• a 12 and A Ij independently represent a single bond, -0- or -N(R 14 )-; and/or
• Prefened compounds of the invention include those in which: X represents a single bond or -C(0)-; G 1 represents halo, cyano, -N 3 , -N0 2 or -A ! -R 9 ;
• G represents cyano, -N 3 or, more preferably, halo. -N0 2 or -A -R 11 ;.
• a 6 represents -N(R 12 )A 9 - or -OA 10 -;
• A represents -C(0)N(R “ )-, -C(0)0- or, more preferably, a single bond or -C(0)-;
• a 10 represents A 9 and, preferably, a smgle bond;
• G 3 represents halo, -N0 2 or -A n -R 13 ;
• a 11 represents -N(R 14 )- or -0-;
• Z J 0; n represents 2; when either of R and R 14 represent optionally substituted Cj -6 alkyl.
• the optional substituent is one or more halo groups; when either of R 1:> and R 16 represent optionally substituted C ]-4 alkyl, the optional substituent is one or more fluoro groups.
• Preferred compounds of the invention include those in which R 1 and (when they represent an aryl or heteroaiyl group) R 2 , R R 4 and/or R 5 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.
• R 2 , R 4 and/or R 5 represent an optionally substituted phenyl, naphthyl, pyrrolyl, furanyl, thienyl, pyrazolyl,
• More prefened compounds include those in wliich: R 6 represents H or optionally substituted C ]-6 alkyl;
• R 7 represents optionally substituted heteroaryl or. more preferably, optionally substituted C ⁇ -6 alkyl or optionally substituted aryl; or R 6 and R 7 are optionally linked as hereinbefore defined.
• R 1 , R 2 , R R 4 , R 3 , R 6 and R 7 groups are preferably selected from cyano, and, more preferably from: halo (e.g. fluoro, chloro or bromo);
• C]_ 6 alkyl which alkyl group may be linear or branched (e.g. C allcyl (mcluding methyl, ethyl, 77-propyl, isopropyl, 77-butyl, isobutyl or /-butyl), 77-pentyl, isopentyl. 77-hexyl or isohexyl), cyclic (e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), part-cyclic (e.g. cyclopropylmethyl). unsaturated (e.g. l-propenyl, 2-propenyl.
• halo e.g. fluoro
• R 17 represents, H or C ⁇ -6 alkyl, such as methyl, etliyl, 77-propyl, isopropyl, 77-butyl. isobutyl or t-butyl (wliich alkyl groups are optionally substituted by one or more halo (e.g. fluoro) groups).
• Prefened values of R are C ⁇ - alkyl and, particularly, hydrogen.
• More prefened compounds include those in which:
• R 1 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;
• R 3 and R 4 independently represent G 1 or, more preferably, H, an aiyl 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 R J and R 4 represents optionally substituted aryl or heteroaryl, and up to one other represents G 1 or, more preferably, hydrogen; when R 3 or R 4 represents an aryl or heteroaiyl group, then the other substituents on the essential benzene ring of the compound of fonnula I (i.e.
• R 2 , R 5 and R 3 or R 4 independently represent hydrogen or
• G 1 e.g. halo (such as chloro), cyano, methyl, methoxy. trifluoromethyl or tri flu oromethoxy ) ;
• R 6 represents H or C ]-4 alkyl, which alkyl group is optionally substituted by one or two G 1 groups:
• R 7 represents C ]- alkyl, which group is optionally substituted by one or two
• G 1 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
• R 6 and R 7 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 G 1 ;
• G 1 represents halo (e.g. chloro) or -A ] -R 9 ;
• a 1 represents a single bond, -OA 5 - or -N(R 10 )A 4 -;
• a 4 and A 5 independently represent a single bond
• B represents G 2 ;
• G 2 represents halo or - A 6 -R ] ] ;
• a 6 represents -0-
• R 9 represents C ]-6 (e.g. C 1-3 ) alkyl, which group is optionally substituted by one or more G 3 groups, or an aryl group, such as a phenyl, or a heteroaiyl group, such as a pyridyl group;
• R 10 represents C 2 alkyl;
• R 11 represents C ]-2 alkyl optionally substituted by one or more G 3 groups
• G 3 represents halo (especially fluoro);
• R 8 represents hydrogen
• R 1 represents a phenyl group, substituted, for example in the 3- or, preferably, 4-position by a single -A'-R 9 group.
• a 1 may represent -OA 3 -, in which A 5 is as hereinbefore defined and is preferably a single bond.
• R 9 may, in such instances, represent C]. 5 (e.g. C 1-4 ) allcyl, such as cyclic C 3 . 5 alltyl (e.g. cyclopenyl) or, preferably, optionally branched propyl, so fonning, for example, a 4-cyclopentoxyphenyl or. more preferably, a 4-isopropoxyphenyl group;
• R " represents halo, cyano, C ⁇ -3 alkyl, C 1-3 alkoxy (which latter two groups are optionally substituted by one or more halo (e.g. fluoro) groups) or, preferably, H;
• R 3 represents a phenyl group, substituted, for example in the 3- or, preferably, 4-position by a single -A ! -R 9 group.
• a 1 may represent a single bond or -OA 5 -.
• a 5 is as hereinbefore defined and is preferably a single bond and R may represent C alkyl, such as branched propyl.
• R 9 may represent a C !- (e.g. C ]-2 ) allcyl group, such as an optionally branched butyl group (e.g.
• R 1 may represent a 4-/e7-t-butylphenyl or, more particularly, a 4-isopropoxyphenyl or 4-trifluoromethylphenyl group;
• R J 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 R to the indole ring, by a single -A'-R 9 group.
• a 1 preferably represents a smgle bond and R 9 represents d -2 allcyl (e.g. methyl) optionally substituted by one or more G groups, in which G represents fluoro, so fonning, for example, a 5- ti'ifluoromethylpyrid-2-yl group;
• R 4 and R 5 independently represent halo, C ⁇ -3 alkyl, C ] -3 alkoxy (which latter two groups are optionally substituted by one or more halo (e.g. fluoro) groups) or, preferably, H;
• R 6 may represent H or a C ]-3 alkyl group, such as a methyl or 77-propyl group, optionally substituted, for example at the terminal position, by a G 1 group.
• G may represent -A'-R 9 , in which A 1 preferably represents a single bond and R preferably represents an aiyl group, such as phenyl, or a heteroaryl group, such as pyridyl (especially 3-pyridyl).
• R 6 may also represent a 3-phenylpropyl. a pyrid-3-ylmethyl or a methyl group;
• R may represent C 1-3 alkyl, such as methyl or 77-propyl, optionally substituted, for example, at the terminal position, by a G 1 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.
• the phenyl group may be substituted in the 3- or. preferably, 4-position, by a B group.
• G 1 may represent -A ⁇ R 9 . in which A 1 preferably represents a -N(R 10 )A 4 group, in which A 4 preferably represents a smgle bond, and R 10 and R 1 1 are each, mdependently.
• B may represent a G ⁇ group, in which G ⁇ is preferably a halo group (such as chloro) or a -A 6 -R ⁇ group.
• G ⁇ is preferably a halo group (such as chloro) or a -A 6 -R ⁇ group.
• a 6 preferably represents -0- and R , ! preferably represents C 1-2 alkyl, such as methyl, optionally substituted by one or more G 3 groups, in wliich G 3 represents halo (especially fluoro).
• R 7 may represent a 3-pyridyl or, more preferably, a dimethylaminopropyl, (4-trifluoromethoxy)phenyl, a 4- chlorophenyl, or a methyl group; when R 6 and R 7 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 fonned is preferably a 5- to 6-membered ring, optionally containing a further heteroatom (e.g. an oxygen heteroatom) so fo ⁇ ning, for example, a pyrrolidinone (e.g. a 1-pyrrolidinone) group or, more preferably, a morpholinyl group (e.g. a 4-morpholinyl group).
• Particularly prefened compounds of the invention include those of the example described hereinafter.
• L 1 represents a suitable leaving group such as chloro, bromo, iodo, a sulfonate group (e.g. -OS(0) 2 CF 3 , -OS(0) 2 CH 3 , -OS(0) 2 PhMe or a nonaflate) or -B(OH) 2 and R 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 , Cul (or Cul/diamine complex), Pd(OAc) 2 , Pd 2 (dba) 3 or NiCl 2 and an optional additive such as Ph 3 P, 2,2'- bis(diphenylphosphino)-l,r-binaphthyl, xantphos, Nal or an appropriate crown ether such as 18-crown-6-benzene, in the presence of an appropriate base such as NaH Et 3 N, pyridine, ⁇ y '-dimethylemyl
• a suitable solvent e.g. dichlorom ethane, dioxane, toluene, ethanol, isopropanol, dimethylfonnamide, ethylene glycol, ethylene glycol dimethyl ether, water, dimethylsulfoxide, acetonirrile, dimethyl
• R 1 represents phenyl and L 1 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 inadiation;
• L J represents L or L ⁇ , in which L " represents a suitable leaving group such as chloro, bromo, iodo, -B(OH) 2 or a protected derivative thereof, for example a 4,4,5, 5-tetramethyl-l,3,2-dioxaborolan-2-yl group, 9- borabicyclo[3.3.1]nonane (9-BBN), -Sn(alkyl) 3 (e.g.
• R 2 , R R 4 and R 5 that are already present in that ring (as appropriate), and X, L 1 , R 1 , R 2 , R 3 , R 4 , R 3 , R 6 , R 7 and R 8 are as hereinbefore defined, with a compound of fonnula VII,
• R 18 represents R 2 , R 3 , R 4 or R 5 (as appropriate), and L 4 represents L 1 (when L 3 is L 2 ) or L 2 (when L 3 is L 1 ) as hereinbefore defmed.
• L and L will be mutually compatible. This reaction may be perfonned, for example in the presence of a suitable catalyst system, e.g.
• a metal such as Cul, PdCl 2 , Pd/C, Pd(OAc) 2 , Pd(Ph 3 P) 2 Cl 2 , Pd(Ph 3 P) 4 , Pd 2 (dba) 3 or NiCl 2 and an additive such as /-Bu 3 P, (C 6 H n ) 3 P, Ph 3 P, AsPh 3 , P(o-Tol) 3 , 1,2- bis(diphenylphosphino)ethane, 2,2'-bis(di-/ ⁇ 7t-butylphosphino)- 1,1'- 2 ⁇ biphenyl, 2,2'-bis(diphenylphosphino)- 1 , 1 '-binaphthyl, 1 ,1 '- bis(diphenylphosphinofenocene), 1 ,3-bis(diphenyl-phosphino)propane or xantphos, together with a suitable
• 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 perfonned), for example to zinc (e.g. using ZnCl 2 ) and the intennediate so fonned 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;
• X, R and L are as herembefore 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. pynolidinopyridine, pyridine, triethylamine, tributylainine, tr nethylamine, dimethylaminopyridine, diisopropylamine, 1,8- diazabicyclo[5.4.0]undec-7-ene, sodium hydroxide, or mixtures thereof) and an appropriate solvent (e.g.
• a suitable base e.g. pynolidinopyridine, pyridine, triethylamine, tributylainine, tr nethylamine, dimethylaminopyridine, diisopropylamine, 1,8- diazabicyclo[5.4.0]undec-7-ene, sodium hydroxide, or mixtures thereof
• This reaction may be perfonned under an inert atmosphere (e.g. under Ar); or
• 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.
• R 2 , R 3 , R 4 , R 5 , R 6 and R 8 are as hereinbefore defined, with a compound of formula IX, as hereinbefore defined, for example under reaction conditions such as those described herembefore in respect of preparation of compounds of fonnula I (process step (iv)) above.
• R and L are as hereinbefore defined, for example under conditions such as those described hereinbefore in respect of preparation of compounds of formula I (process step (iii)) above;
• R , R " , R , R , R 3 and R are as hereinbefore defined, with an appropriate reagent for the conversion of the hydroxyl group to the sulfonate group (e.g. tosyl chloride, mesyl chloride, triflic anhydride and the like) under conditions known to those skilled in the art.
• an appropriate reagent for the conversion of the hydroxyl group to the sulfonate group e.g. tosyl chloride, mesyl chloride, triflic anhydride and the like
• Compounds of formula VI in which represents L " may be prepared by reaction of a compound of fonnula VI in which L J represents L 1 , with an appropriate reagent for the conversion of the L 1 group to the L 2 group. This conversion may be perfonned by methods known to those skilled in the art, for example: i) ' compounds of formula VI, in which L 3 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 fonnula VI in which L 3 represents L 1 , for example under reaction conditions such as those described hereinbefore in respect of preparation of compounds of formula I (process step (iii)) above; ii) compounds of fonnula VI, in which L 3 represents -B(OH) 2 may be prepared by reaction of a conesponding compound of formula VI in which L 3 represents halo by reaction with, for example, boronic acid or
• conversion of a bromo group to an iodo group may be perfonned in the presence of Nal, optionally in the presence of a suitable catalyst (e.g. Cul) and/or a catalytic amount of base (e.g. NW.-dimethyl-l,2- diaminoethane) in the presence of a suitable solvent such as one described hereinbefore in respect of preparation of compounds of fonnula I (process step (i)).
• a suitable catalyst e.g. Cul
• a catalytic amount of base e.g. NW.-dimethyl-l,2- diaminoethane
• Conversions of the L 4 group and the L J group in the compounds of formulae VII and XI, respectively, may be perfonned in a similar mamier to that described above in respect of converting the L group in compounds of fonnula VI.
• R 2 , R 3 , R 4 , R 5 and R 8 are as hereinbefore defined, with a reagent, or mixture of reagents known to be a source of halide (e.g. bromide or iodide) ions.
• a reagent or mixture of reagents known to be a source of halide (e.g. bromide or iodide) ions.
• N-bromosuccinimide may be employed, for iodide ions, iodine or a mixture of ⁇ al and N- chlorosuccinimide may be employed, for chloride ions, N- chloiOSuccinhnide may be employed and for fluoride ions, 1- (chloromethyl)-4-fluoro-l ,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) may be employed.
• This reaction may be canied out in a suitable solvent (e.g. acetone, benzene or dioxane) under conditions known to the skilled person;
• L 1 , R 2 , R 3 , R 4 , R 3 and R 8 are as herembefore defined with a compound of fonnula VII as hereinbefore defined, for example under reaction conditions such as those described hereinbefore in respect of preparation of compounds of fonnula I (process step (iii)) above; or
• R , R , R , R and R are as hereinbefore defined, with an appropriate reagent for the conversion of the hydroxyl group to a sulfonate group as described hereinbefore.
• Compounds of fonnula XII may be prepared for example by reaction of a compound of fonnula X, as hereinbefore defined, with a compound of fonnula XVIII,
• R 6 is as hereinbefore defined, for example under reaction conditions such as those described hereinbefore in respect of preparation of compounds of fonnula I (process step (ii)) above;
• Indoles of fonnulae 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 Chemistiy” by J. A. Joule. K. Mills and G. F. Smith, 3 rd edition, published by Chapman & Hall or "Comprehensive Heterocyclic Chemistry IF by A. R. Katritzky, C. W. Rees and E. F. V. Scriven, Pergamon Press, 1996) and/or made according to the followmg general procedures.
• a standard heterocyclic chemistry textbook e.g. "Heterocyclic Chemistiy” by J. A. Joule. K. Mills and G. F. Smith, 3 rd edition, published by Chapman & Hall or "Comprehensive Heterocyclic Chemistry IF by A. R. Kat
• XI, XII and XV may be prepared by reaction of a compound of formula XIX,
• SUB represents the substitution pattern that is present in the compound of fonnula II, XI, XII or XV to be fonned
• (G) represents either a -N(R 6 )C(0)R 7 group (as required for formation of compounds of fonnulae II and XI), a -N(R 6 )H group (as required for formation of compounds of fonnula XII) or hydrogen (as required for fonnation of compounds of fonnula XV) and R 8 is as hereinbefore defined, under Fischer indole synthesis conditions known to the person skilled the art.
• R 2 , R 3 , R 4 and R 5 are as hereinbefore defined with a compound of fonnula XXI,
• R 8 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 thennally mduced cyclisation).
• R ⁇ represents a C] -6 alkyl group
• R y represents either R 1 as hereinbefore defined (as required for fonnation of compounds of fonnula XIV), hydrogen (as required for fonnation of compounds of formula XVII) or a nitrogen-protected derivative thereof
• R 2 , R 3 , R 4 , R 5 and R 8 are as hereinbefore defined and, under standard cyclisation conditions known to those skilled in the art.
• R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 in final compounds of the invention or relevant intennediates 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 substimtions, reductions, oxidations, alkylations, hydrolyses, esterifications, and etherifications.
• the precursor groups can be changed to a different such group, or to the groups defined in fonnula I, at any time during the reaction sequence. For example, in cases where R does not initially represent hydrogen (so providing an ester functional group), the skilled person will appreciate that at any stage durmg the synthesis (e.g.
• the relevant substituent may be hydrolysed to fonn a carboxylic acid functional group (in which case R will be hydrogen).
• R will be hydrogen
• the skilled person may also refer to "Comprehensive Organic Functional Group Transformations" by A. R. Katritzky, 0. Meth-Cohn and C. W. Rees, Pergamon Press, 1995.
• Compounds of the invention may be isolated from their reaction mixtures using conventional techniques.
• the protection and deprotection of functional groups may take place before or after a reaction in the above-mentioned schemes.
• Protecting groups may be removed i 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 compomids using standard deprotection techniques.
• compounds of the invention may possess phannacological activity as such, certain pharmaceutically-acceptable (e.g. "protected") derivatives of compounds of the invention may exist or be prepared wliich may not possess such activity, but may be administered parenterally or orally and thereafter be metabolised in the body to fonn compounds of the invention.
• Such compounds (which may possess some phannacological activity, provided that such activity is appreciably lower than that of the "active" compounds to which they are metabolised) may therefore be described as "prodrugs" of compounds of the invention.
• prodrug of a compound of the invention we include compounds that fonn a compound of the invention, in an experimentally-detectable amount, within a predetennined time (e.g. about 1 hour), following oral or parenteral administration. All prodrugs of the compounds of the invention are included within the scope of the invention.
• certain compounds of the invention may possess no or minimal phannacological activity as such, but may be administered parenterally or orally, and thereafter be metabolised in the body to fonn compounds of the invention that possess phannacological activity as such (including, but not limited to, conesponding compounds of fonnula I. in which R 6 represents hydrogen).
• Such compounds may also be described as "prodrugs”.
• the compounds of the invention are useful because they possess pharmacological activity, and/or are metabolised in the body following oral or parenteral administration to fonn compounds which possess phannacological 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 mPGES-1 or a complex of which the mPGES-1 enzyme fonns a part, and/or may elicit a mPGES-1 modulating effect, for example as may be demonstrated in the test described below.
• Compounds of the invention may thus be useful in the treatment of those conditions in which inhibition of a PGES, and particularly mPGES-1 , is required.
• LTC 4 leukotriene C 4
• FLAP 5-lipoxygenase- activating protein
• inflammation will be understood by those skilled in the art to include any condition characterised by a localised or a systemic protective response, which may be elicited by physical trauma, infection, chronic diseases, such as those mentioned hereinbefore, and/or chemical and/or physiological reactions to external stimuli (e.g. as part of an allergic response). Any such response, which may serve to destroy, dilute or sequester both the injurious agent and the injured tissue, may be manifest by, for example, heat, swelling, pain, redness, dilation of blood vessels and/or increased blood flow, invasion of the affected area by white blood cells, loss of function and/or any other symptoms known to be associated with inflammatory conditions .
• inflammation will thus also be understood to include any inflammatory disease, disorder or condition per se, any condition that has an inflammatory component associated with it, and/or any condition characterised by inflammation as a symptom, including inter alia acute, chronic, ulcerative, specific, allergic and necrotic inflammation, and other fo ⁇ ns of inflammation known to those skilled in the art.
• the tenn thus also includes, for the purposes of this mvention, inflammatory pain, pain generally and/or fever.
• 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, dysmenonhea, bums, 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, ulceris, 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, rliinitis, ulcers, coronary heart disease, sarcoidosis and any other disease with an inflammatory component.
• Other diseases that may be mentioned include inflammatoiy pain, hyperprostaglandin E syndrome, classic Bartter syndrome, Hodgkin's disease and persistent ductus (PDA).
• Compounds of the mvention may also have effects that are not linked to inflammatoiy 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 healmg of fractures, in subjects.
• a method of treatment of a disease which is associated with, and/or which can be modulated by inhibition of LTC 4 , FLAP and/or, preferably, a PGES (such as mPGES-1), and/or a method of treatment of a disease in wliich inhibition of the activity of LTC 4 , 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.
• a PGES such as mPGES-1
• Patients include mammalian (including human) patients.
• the tenn "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).
• Compomids of the invention will normally be administered orally, intravenously, subcutaneously, buccally, rectally, dermally, nasally, tracheally, bronchially, sublmgually, by any other parenteral route or via inhalation, in a pharmaceutically acceptable dosage fonn.
• Compounds of the invention may be administered alone, but are preferably admhiistered by way of known pharmaceutical formulations, includmg tablets, capsules or elixirs for oral administration, suppositories for rectal administration, sterile solutions or suspensions for parenteral or intramuscular administration, and the like.
• Such fonnulations may be prepared in accordance with standard and/or accepted phannaceutical practice.
• a phannaceutical fonnulation including a compound of the invention, as hereinbefore defined, i admixture with a phannaceutically acceptable adjuvant, diluent or carrier.
• Compounds of the invention may also be combined with other therapeutic agents that are useful in the treatment of inflammation (e.g. NSAIDs and coxibs).
• a combination product comprising:
• each of components (A) and (B) is formulated in admixture with a pharmaceutically-acceptable adjuvant, diluent or canier.
• 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 fonnulations comprises a compound of the mvention, 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 fonnulation including a compound of the invention and the other therapeutic agent).
• a phannaceutical fonnulation including a compound of the invention, as hereinbefore defmed, another therapeutic agent that is useful in the treatment of mflammation, and a phannaceutically-acceptable adjuvant, diluent or canier;
• kit of parts comprising components: (a) a pharmaceutical formulation including a compound of the invention, as hereinbefore defined, in admixture with a phannaceutically- acceptable adjuvant, diluent or canier; and (b) a phannaceutical fonnulation including another therapeutic agent that is useful in the treatment of inflammation in admixture with a pharmaceutically-acceptable adjuvant, diluent or canier, wliich components (a) and (b) are each provided in a fonn that is suitable for administration in conjunction with the other.
• Compounds of the invention may be administered at varying doses.
• Oral, pulmonary and topical dosages may range from between about 0.01 mg/kg of body weight per day (mg/kg/day) to about 100 mg/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.
• the compositions typically contain between about 0.01 mg to about 500 mg, and preferably between about 1 mg to about 100 mg, of the active ingredient.
• the most prefened doses will range from about 0.001 to about 10 mg/kg/hour during constant rate infusion.
• compounds may be admhiistered in a single daily dose, or the total daily dosage may be admhiistered in divided doses of two, three or four times daily.
• the physician or the skilled person, will be able to determine the actual dosage which will be most suitable for an individual patient, which is likely to vary with the route of administration, the type and severity of the condition that is to be treated, as well as the species, age, weight, sex, renal function, hepatic function and response of the particular patient to be treated.
• the above-mentioned dosages are exemplary of the average case; there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.
• Compounds of the invention may have the advantage that they are effective, and preferably selective, inhibitors of prostaglandin E synthases (PGES) and particularly microsomal prostaglandin E synthase-1 (mPGES-1).
• the compounds of the mvention may reduce the fonnation of the specific arachidonic acid metabolite PGE 2 without reducing the fonnation 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 pharmacolcinetic profile (e.g. higher oral bioavailability and/or lower clearance) than, and/or have other useful phannacological, physical, or chemical properties over, compounds known in the prior art, whether for use in the above-stated indications or otherwise.
• a better pharmacolcinetic profile e.g. higher oral bioavailability and/or lower clearance
• mPGES-1 catalyses the reaction where the substrate PGH 2 is converted to PGE 2 .
• mPGES-1 is expressed in E. coli and the membrane fraction is dissolved in 20mM NaPi-buffer pH 8.0 and stored at
• the stop solution consists of H 2 0 / MeCN
• the mobile phase consists of H 2 0 / MeCN (7/3), containing TFA (0.056%), and absorbance is measured at 195 nm with a
• 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 %).
• 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.
• Morpholine (34.5 ⁇ L, 0.4 l nol), followed by anhydrous toluene (10 mL) was added under argon to a mixture of Pd 2 (dba) 3 (6 mg, 0.0066 mmol), BINAP (6.12 mg, 0.0099 mmol), Cs 2 C0 3 (150 mg, 0.46 mmol) and 3- bromo-l-(4-isopropoxyphenyl)-5-(4-(trifluoromethyl)phenyl)h dole-2- carboxylic acid ethyl ester (180 mg, 0.33 mmol; see step (b)).
• the mixture was stined 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 Pd 2 (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 Et 2 0, and filtered through Celite ® . The filtrate was concentrated and the residue purified by chromatography to afford the sub-title compound (116 mg, 64%).
• the sub-title compound was prepared from 5-bromo-3-nitro-lH-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-l-(4-isopropoxyphenyl)-3-nitro- lH-indole-2-carboxylic acid ethyl ester (see step (b) above) and 4-te/-t- butylphenylboronic acid instead of 4-isopropoxyphenylboronic acid.
• the sub-title compound was prepared in accordance with the procedure described in Example 1(c) using 3-iodo-5-(5-trifluoromethylpyrid-2-yl)-lH- 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 l-(4-cyclopentoxyphenyl)-3-iodo-5-(5- trifluoromethylpyrid-2-yl)-lH-indole-2-carboxylic acid ethyl ester (see step (d) above) and 4-dimethylaminobutyramide instead of acetamide.
• the sub-title compound was prepared in accordance with the procedure described in Example 1 (d) using l-(4-cyclopentoxyphenyl)-3-iodo-5-(5- trifluoromethylpyrid-2-yl)-lH-indole-2-carboxylic acid ethyl ester (see Example 9(d)) and pynolidin-2-one instead of acetamide.
• the title compound was prepared by hydrolysis of l-(4-cyclopentoxy- phenyl)-3-(2-oxopynolidin-l-yl)-5-(5-trifluoromethylpyrid-2-yl)-lH- indole-2-carboxylic acid ethyl ester (see step (a) above) in accordance with the procedure described in Example 1(e).
• the sub-title compound was prepared in accordance with the procedure described in Example 1 (c) using 3-iodo-5-(5-trifluoromethylpyridin-2-yl)- lH-indole-2-carboxylic acid ethyl ester (see Example 9 (c)) and 4- isopropoxyphenylboronic acid.
• Example 13 l-(4-Isopropox) ⁇ henyl)-3-nicotinamide-5-(5-trifluoromethylpyridin-2-yl)- lH-indole-2-carboxylic acid was prepared hi accordance with the procedures described herein.
• Example 7 730 nM
• Example 12 5300 nM

Landscapes

• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Life Sciences & Earth Sciences (AREA)
• Veterinary Medicine (AREA)
• Medicinal Chemistry (AREA)
• Public Health (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• General Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Engineering & Computer Science (AREA)
• Physical Education & Sports Medicine (AREA)
• Rheumatology (AREA)
• Neurology (AREA)
• Orthopedic Medicine & Surgery (AREA)
• Pulmonology (AREA)
• Neurosurgery (AREA)
• Biomedical Technology (AREA)
• Oncology (AREA)
• Communicable Diseases (AREA)
• Pain & Pain Management (AREA)
• Dermatology (AREA)
• Diabetes (AREA)
• Heart & Thoracic Surgery (AREA)
• Urology & Nephrology (AREA)
• Cardiology (AREA)
• Endocrinology (AREA)
• Immunology (AREA)
• Emergency Medicine (AREA)
• Vascular Medicine (AREA)
• Hematology (AREA)
• Hospice & Palliative Care (AREA)
• Psychiatry (AREA)
• Reproductive Health (AREA)
• Obesity (AREA)
• Ophthalmology & Optometry (AREA)

Priority Applications (9)

Applications Claiming Priority (2)

Publications (1)

Family

ID=34956078

Family Applications (1)

Country Status (15)

Cited By (21)

Families Citing this family (2)

Citations (2)

Family Cites Families (23)

• 2005
  • 2005-06-17 KR KR1020077001306A patent/KR20070029809A/ko not_active Withdrawn
  • 2005-06-17 DE DE602005011452T patent/DE602005011452D1/de not_active Expired - Fee Related
  • 2005-06-17 ES ES05751820T patent/ES2321422T3/es not_active Expired - Lifetime
  • 2005-06-17 JP JP2007516044A patent/JP2008502670A/ja not_active Withdrawn
  • 2005-06-17 BR BRPI0512253-8A patent/BRPI0512253A/pt not_active IP Right Cessation
  • 2005-06-17 CN CNA2005800284017A patent/CN101006054A/zh active Pending
  • 2005-06-17 AT AT05751820T patent/ATE416161T1/de not_active IP Right Cessation
  • 2005-06-17 MX MXPA06014536A patent/MXPA06014536A/es unknown
  • 2005-06-17 CA CA002570531A patent/CA2570531A1/en not_active Abandoned
  • 2005-06-17 AU AU2005254783A patent/AU2005254783A1/en not_active Abandoned
  • 2005-06-17 WO PCT/GB2005/002396 patent/WO2005123674A1/en not_active Ceased
  • 2005-06-17 EP EP05751820A patent/EP1778633B1/en not_active Expired - Lifetime
  • 2005-06-17 US US11/629,627 patent/US20080188473A1/en not_active Abandoned
  • 2005-06-17 RU RU2007101703/04A patent/RU2007101703A/ru not_active Application Discontinuation
• 2006
  • 2006-11-27 IL IL179607A patent/IL179607A0/en unknown

Patent Citations (2)

Also Published As

Similar Documents

Legal Events