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Definitions

• This invention relates to compounds that inhibit or modulate the activity of p38 MAP kinase, to the use ofthe compounds in the treatment or prophylaxis of disease states or conditions mediated by p38 MAP kinase, and to novel compounds having p38 MAP kinase inhibitory or modulating activity. Also provided are pharmaceutical compositions containing the compounds and novel chemical intermediates.
• Protein kinases constitute a large family of structurally related enzymes that are responsible for the control of a wide variety of signal transduction processes within the cell (Hardie, G. and Hanks, S. (1995) The Protein Kinase Facts Book. I and II, Academic Press, San Diego, CA).
• the kinases may be categorized into families by the substrates they phosphorylate (e.g., protein-tyrosine, protein-serine/threonine, lipids, etc.).
• Protein kinases may be characterized by their regulation mechanisms. These mechanisms include, for example, autophosphorylation, transphosphorylation by other kinases, protein-protein interactions, protein-lipid interactions, and protein- polynucleotide interactions. An individual protein kinase may be regulated by more than one mechanism.
• Kinases regulate many different cell processes including, but not limited to, proliferation, differentiation, apoptosis, motility, transcription, translation and other signaling processes, by adding phosphate groups to target proteins. These phosphorylation events act as molecular on/off switches that can modulate or regulate the target protein biological function. Phosphorylation of target proteins occurs in response to a variety of extracellular signals (hormones, neurotransmitters, growth and differentiation factors, etc.), cell cycle events, environmental or nutritional stresses, etc.
• the appropriate protein kinase functions in signaling pathways to activate or inactivate (either directly or indirectly), for example, a metabolic enzyme, regulatory protein, receptor, cytoskeletal protein, ion channel or pump, or transcription factor.
• Uncontrolled signaling due to defective control of protein phosphorylation has been implicated in a number of diseases, including, for example, inflammation, cancer, allergy/asthma, disease and conditions ofthe immune system, disease and conditions ofthe central nervous system, and angiogenesis.
• the mitogen-activated protein (MAP) kinase family consists of a series of structurally related proline-directed serine/threonine kinases that are activated either by growth factors (such as EGF) and phorbol esters (ERK), or by IL-1, TNF or stress (p38, JNK). These kinases mediate the effects of numerous extracellular stimuli on a wide array of biological processes, such as cell proliferation, differentiation and death.
• EGF extracellular signal-regulated kinases
• JNK c-Jun NH 2 - terminal kinases
• p38 MAP kinases Three groups of mammalian MAP kinases have been studied in detail: the extracellular signal-regulated kinases (ERK), the c-Jun NH 2 - terminal kinases (JNK) and the p38 MAP kinases.
• p38 MAP kinase There are five known human isoforms of p38 MAP kinase, p38 ⁇ , p38 ⁇ , p38 ⁇ 2, p38 ⁇ and p38 ⁇ .
• the p38 kinases which are also known as cytokine suppressive anti-inflammatory drug binding proteins (CSBP), stress activated protein kinases (SAPK) and RK, are responsible for phosphorylating (Stein et al, Ann. Rep. Med Chem., 31, 289-298 (1996)) and activating transcription factors (such as ATF-2, MAX, CHOP and C/ERPb) as well as other kinases (such as MAPKAP-K2/3 or MK2/3), and are themselves activated by physical and chemical stress (e.g.
• IL-1 and TNF are also known to stimulate the production of other proinflammatory cytokines such as IL-6 and IL-8.
• Interleukin-1 IL-1
• Tumor Necrosis Factor TNF
• IL-1 has been demonstrated to mediate a variety of biological activities thought to be important in immunoregulation and other physiological conditions such as inflammation (e.g. Dinarello, et al, Rev. Infect. Disease, 6: 51 (1984)).
• the myriad of known biological activities of IL-1 include the activation of T helper cells, induction of fever, stimulation of prostaglandin or collagenase production, neutrophil chemotaxis, induction of acute phase proteins and the suppression of plasma iron levels.
• rheumatoid arthritis (Arend et al, Arthritis & Rheumatism 38(2): 151-160, osteoarthritis, endotoxemia and/or toxic shock syndrome, other acute or chronic inflammatory disease states such as the inflammatory reaction induced by endotoxin or inflammatory bowel disease; tuberculosis, atherosclerosis, Hodgkin's disease (Benharroch et al, Euro.
• Cytokine Network 7(1): 51-57 muscle degeneration, cachexia, psoriatic arthritis, Reiter's syndrome, gout, traumatic arthritis, rubella arthritis, acute synovitis and Alzheimer's disease.
• Evidence also links IL-1 activity to diabetes and pancreatic B cells (Dinarello, J Clinical Immunology, 5: 287-297 (1985)). Because inhibition of p38 leads to inhibition of IL-1 production, it is envisaged that p38 inhibitors will be useful in the treatment ofthe above listed diseases.
• TNF production has been implicated in mediating or exacerbating a number of diseases including rheumatoid arthritis (Maini et al, APMIS, 105(4): 257-263), rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions; sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoisosis, bone resorption diseases, reperfusion injury, graft vs.
• p38 inhibitors will be useful in the treatment ofthe above listed diseases.
• Interleukin-8 is a chemotactic factor produced by several cell types including mononuclear cells, fibroblasts, endothelial cells, and keratinocytes. Its production from endothelial cells is induced by IL-1, T ⁇ F, or lipopolysachharide (LPS). IL-8 stimulates a number of functions in vitro. It has been shown to have chemoattractant properties for neutrophils, T -lymphocytes, and basophils. In addition it induces histamine release from basophils from both normal and atopic individuals as well as lysozomal enzyme release and respiratory burst from neutrophils.
• IL-1 interleukin-1
• T ⁇ F lipopolysachharide
• IL-8 has also been shown to increase the surface expression of Mac-1 (CD 11 blCD 18) on neutrophils without de novo protein synthesis; this may contribute to increased adhesion ofthe neutrophils to vascular endothelial cells.
• Mac-1 CD 11 blCD 18
• Many diseases are characterized by massive neutrophil infiltration.
• Conditions associated with an increased in IL-8 production (which is responsible for chemotaxis of neutrophil into the inflammatory site) would benefit from treatment with compounds which are suppressive of IL-8 production.
• COPD Chronic Obstructive Pulmonary Disease
• IL-8 Other conditions linked to IL-8 include acute respiratory distress syndrome (ARDS), asthma, pulmonary fibrosis and bacterial pneumonia.
• ARDS acute respiratory distress syndrome
• IL-1 and TNF affect a wide variety of cells and tissues and these cytokines as well as other leukocyte derived cytokines are important and critical inflammatory mediators of a wide variety of disease states and conditions. The inhibition of these cytokines is of benefit in controlling, reducing and alleviating many of these disease states.
• Inhibition of signal transduction via p38 which in addition to IL-1, TNF and IL-8 described above is also required for the synthesis and/or action of several additional pro-inflammatory proteins (i.e., IL-6, GM-CSF, COX-2, collagenase and stromelysin), is expected to be a highly effective mechanism for regulating the excessive and destructive activation ofthe immune system. This expectation is supported by the potent and diverse anti-inflammatory activities described for p38 kinase inhibitors (Badger, et al, J. Pharm. Exp. Thera., 279: 1453-1461(1996); Griswold, et al, Pharmacol. Comm., 7: 323-229 (1996)).
• WO 01/47922 discloses a class of substituted azindoles and their use in treating disease states capable of being modulated by inhibition of protein kinases, and in particular the Syk kinase, a 72-kDa cytoplasmic protein tyrosine kinase.
• WO 02/10137 (Signal Pharmaceuticals Inc.) discloses a class of indazole compounds as inhibitors of JNK kinases. The compounds are disclosed as having a variety of therapeutic uses such as the treatment of arthritis.
• WO 01/02369 also relates to indazole compounds that modulate and/or inhibit the activity of certain protein kinases, particularly tyrosine kinases.
• the compounds have a substituted or unsubstituted aryl or hetero-aryl group in the 3 position ofthe indazole ring.
• WO 00/71535 discloses indole-type compounds as inhibitors of p38 kinase.
• the 6-membered ring in the indole-like nucleus ofthe compounds is linked to a piperidine or piperazine group via a short linker group.
• WO 00/46198 discloses a class of indole derivatives having anti- inflammatory activity in which the compounds have an aryl or hetero-aryl ring linked to the 1 -position ofthe indole nucleus by a CH 2 or SO 2 linking group. The compounds are disclosed as being antagonists ofthe pro-inflammatory cytokine MCP-1.
• WO 93/1408 discloses 1,3,4-triaryl imidazoles as inhibitors of ⁇ 38 MAP kinase.
• WO 99/15164 discloses various bis-benzamidophenyl derivatives compounds which exhibit inhibition of p38 activity.
• WO 99/32111 (Bayer) discloses a series of diarylurea compounds which act as p38 MAP kinase inhibitors.
• WO 99/00357 discloses a further class of diarylurea compounds as p38 MAP kinase inhibitors.
• WO 99/43651 and WO99/43654 disclose substituted indoles as phospholipase inhibitors useful in treating or preventing inflammatory conditions.
• the invention provides a class of compounds, some known and some novel, that have p38 MAP kinase inhibiting or modulating activity, and which it is envisaged will be useful in preventing or treating disease states or conditions mediated by the p38 MAP kinases. Accordingly, in a first aspect, the invention provides a compound for use in the prophylaxis or treatment of a disease state or condition mediated by a p38 MAP kinase; the compound being ofthe general formula (I):
• U, T, N and W are each a nitrogen atom or a group CR 4 provided that no more than three of U, T, N and W are nitrogen atoms;
• R° is hydrogen, C ⁇ - 4 hydrocarbyl, halogen or a group -A-R 3 ;
• R 1 is hydrogen, C ⁇ - hydrocarbyl or a group -A-R 3 ; provided that only one of R° and R 1 is a group -A-R 3 ;
• R 2 is hydrogen, C ⁇ . 4 hydrocarbyl or halogen
• A is a carbon- or heteroatom-containing linker group having a linking chain length of one or two atoms;
• R 3 is a monocyclic or bicyclic heteroaryl group containing from five to twelve ring members; each group R 4 is independently selected from hydrogen, hydroxy, halogen, nitro, cyano, a monocyclic heterocyclic group having up to seven ring members, a group ⁇ (R 5 ) 2 , a group C(O)N(R 6 ) 2 , a group SO 2 N(R 6 ) 2 , a group R a -R b and a group Y; provided that no more than one group Y is present;
• R a is a bond, O, S, SO, SO 2 , NH or N-C M hydrocarbyl
• R b is Ci-8 hydrocarbyl optionally interrupted by O, S, SO, SO 2 , NH or N- . hydrocarbyl and optionally substituted by one or more substitutents selected from hydroxy, amino, mono- or di-C ⁇ - hydrocarbylamino, C M hydrocarbyloxy, oxo, Ci ⁇ hydrocarbylthio and halogen; each group R 5 is independently selected from hydrogen, C ⁇ alkyl, C ⁇ - acyl and C alkylsulphonyl; each group R 6 is independently selected from hydrogen and C ⁇ - 4 hydrocarbyl;
• Y is a group -N(R 7 )-C(O)-R 8 or -N(R 7 )-SO 2 -R 8 ;
• R 7 is hydrogen, C ⁇ - 4 hydrocarbyl or a group C(O)-R 8 or SO 2 -R 8 ;
• R 8 is selected from Cj.io hydrocarbyl, Ci-io hydrocarbylamino, Cno hydrocarbylthio, Cno hydrocarbyloxy, and aryl, arylamino, arylthio and aryloxy groups, the aryl moieties of which are carbocyclic or heterocyclic and have from five to twelve ring members, each substituent group R 8 being optionally substituted by one or more groups R 4 other than Y; or R 7 and R 8 together with the nitrogen and carbon or sulphur atoms to which they are attached are linked to form a ring structure of 4 to 7 ring members; wherein R° is other than a 2-(2,4 ⁇ diamino-6-triazinyl)ethyl group when, in
• Compounds ofthe formula (I) as defined above have activity in modulating or inhibiting p38 MAP kinase activity. As such, it is anticipated that the compounds possessing such activity will be useful therapeutic agents in the prophylaxis or treatment of diseases where the disease or condition is one in which the activity of p38 MAP kinase initiates or facilitates development ofthe disease.
• conditions ameliorated by the inhibition of p38 MAP kinase include, but are not limited to, rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gouty arthritis, traumatic arthritis, rubella arthritis, psoriatic arthritis, and other arthritic conditions; Alzheimer's disease; toxic shock syndrome, the inflammatory reaction induced by endotoxin or inflammatory bowel disease; tuberculosis, atherosclerosis, muscle degeneration, Reiter's syndrome, gout, acute synovitis, sepsis, septic shock, endotoxic shock, gram negative sepsis, adult respiratory distress syndrome, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoisosis, bone resorption diseases, reperfusion injury, graft vs.
• allograft rejections fever and myalgias due to infection, such as influenza, cachexia, in particular cachexia secondary to infection or malignancy, cachexia secondary to acquired immune deficiency syndrome (AIDS), AIDS, ARC (AIDS related complex), keloid formation, scar tissue formation, Crohn's disease, ulcerative colitis, pyresis, chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), asthma, pulmonary fibrosis and bacterial pneumonia.
• AIDS acquired immune deficiency syndrome
• AIDS AIDS
• ARC AIDS related complex
• keloid formation scar tissue formation
• Crohn's disease Crohn's disease
• COPD chronic obstructive pulmonary disease
• ARDS acute respiratory distress syndrome
• asthma pulmonary fibrosis and bacterial pneumonia.
• the invention provides the use of a compound ofthe formula (I) as defined herein for the manufacture of a medicament for the prophylaxis or treatment of a disease state or condition mediated by a p38 MAP kinase.
• the invention provides a method for the prophylaxis or treatment of a disease state or condition mediated by a p38 MAP kinase, which method comprises administering to a subject in need thereof a compound ofthe formula (I) as defined herein.
• the invention also provides a method of inhibiting a p38 MAP kinase, which method comprises contacting the p38 MAP kinase with a kinase-inhibiting compound ofthe formula (I) as defined herein.
• the invention further provides a method of modulating a cellular process by inhibiting the activity of a p38 MAP kinase using a compound ofthe formula (I) as defined herein.
• hydrocarbyl is a generic term encompassing aliphatic, alicyclic and aromatic groups having an all-carbon backbone. Examples of such groups include alkyl, cycloalkyl, cycloalkenyl, carbocyclic aryl, alkenyl, alkynyl, cycloalkylalkyl, cycloalkenylalkyl, and carbocyclic aralkyl, aralkenyl and aralkynyl groups. Such groups can be unsubstituted or substituted by one or more substituents as defined herein. The examples and preferences expressed below apply to each ofthe hydrocarbyl substituent groups or hydrocarbyl-containing substituent groups referred to in the various definitions of substituents for compounds ofthe formula (I) unless the context indicates otherwise.
• hydrocarbyl group being "optionally interrupted" by one or more atoms or groups (e.g. by O, S, SO, SO 2 , NH or N-C ⁇ - 4 hydrocarbyl in the case ofthe group R ), this is intended to refer to the case in which one or more ofthe said atoms or groups is interposed between adjacent carbon atoms in the carbon backbone ofthe hydrocarbyl group.
• a -CH 2 -CH 2 -O-CH 2 -CH - group can be viewed as a butylene group interrupted by an oxygen atom.
• preferred aliphatic hydrocarbyl groups are those having from 1 to 8 carbon atoms, more typically from 1 to 6 carbon atoms, more preferably from 1 to 4 carbon atoms.
• Preferred alicyclic hydrocarbyl groups are those including up to 10 ring members, and more usually up to six ring members.
• Preferred aromatic carbocyclic groups are those having up to 10 ring members, more preferably up to 6 ring members.
• alkyl covers both straight chain and branched chain alkyl groups. Unless the context indicates otherwise, the term “alkyl” refers to groups having 1 to 8 carbon atoms, and typically from 1 to 6 carbon atoms, for example from 1 to 4 carbon atoms. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl butyl, 3 -methyl butyl, and n-hexyl and its isomers.
• Examples of cycloalkyl groups are those having from 3 to 10 ring atoms, particular examples including those derived from cyclopropane, cyclobutane, cyclopentane, cyclohexane and cycloheptane, bicycloheptane and decalin.
• alkenyl groups include, but are not limited to, ethenyl (vinyl), 1- propenyl, 2-propenyl (allyl), isopropenyl, butenyl, buta-l,4-dienyl, pentenyl, and hexenyl .
• Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl and cyclohexenyl.
• Examples of alkynyl groups are those having from 2 to 8 carbon atoms, more typically from 2 to 6 carbon atoms, for example from 2 to 4 carbon atoms.
• Examples of alkynyl groups include, but are not limited to, ethynyl and 2-propynyl (propargyl) groups.
• carbocyclic aryl groups examples include phenyl, naphthyl, indenyl, and tetrahydronaphthyl.
• cycloalkylalkyl, cycloalkenylalkyl, carbocyclic aralkyl, aralkenyl and aralkynyl groups include phenethyl, benzyl, naphthylmethyl, styryl, phenylethynyl, cyclohexylmethyl, cyclopentylmethyl, cyclobutlymethyl, cyclopropylmethyl and cyclopentenylmethyl groups.
• small alkyl groups are generally preferred, presently preferred groups including methyl and ethyl, with methyl being particularly preferred.
• aryl as used herein (for example in the terms “arylamino” and
• arylthio refers to a carbocyclic or heterocyclic group having aromatic character.
• the aryl group can be a monocyclic or bicyclic group and can be unsubstituted or substituted with one or more substituents.
• the term "aryl” embraces polycyclic (e.g. bicyclic) ring systems wherein one or more rings are non-aromatic, provided that at least one ring is aromatic. Examples of non-heterocyclic aryl groups include phenyl, indenyl, tetrahydronaphthyl and naphthyl, and such groups may be unsubstituted or substituted with one or more substituents. Examples of heterocyclic groups axe those set out herein in relation to the group R .
• monocyclic heterocyclic group refers to both aromatic and non-aromatic heterocyclic groups.
• aromatic heterocyclic groups are the monocyclic groups listed in respect of substituent group R .
• non-aromatic heterocyclic groups include, but are not limited to, rings containing up to three heteroatoms selected from nitrogen, sulphur and oxygen. Typically at least one nitrogen atom will be present.
• Particular examples of such groups include piperidine, piperazine, N- methylpiperazine, morpholine, pyrrolidine, imidazoline, imidazolidine, thiazoline, thiazolidine, oxazoline, oxazolidine and tetrahydrofuran.
• Preferred non-aromatic heterocyclic groups include morpholine and piperidine, particularly morpholine.
• halogen as used herein includes fluorine, chlorine, bromine and iodine, but fluorine and chlorine are generally preferred as substituents.
• the compounds ofthe formula (I) are indoles or aza-indoles containing one, two or three nitrogen atoms in the six membered ring.
• the six membered ring contains no more than two nitrogen atoms, and preferably no more than one. Indoles are particularly preferred.
• T and V are each a group CR 4 , and preferably at least one (e.g. U) and more preferably both of U and W are each a group CR 4 .
• one of U and W is a group CR 4 , and preferably T and V are also both CR 4 .
• U can be a group CR 4 whilst W is a nitrogen atom, or both U and W can be CR 4 .
• the group R can be hydrogen or a group Y or a relatively small substituent such as hydroxy, halogen, nitro, cyano, a monocyclic heterocyclic group having up to seven ring members, a group N(R 5 ) 2 , a group C(O)N(R 6 ) 2 , a group SO 2 N(R 6 ) 2 or a group R a -R b as hereinbefore defined. Only one group Y is typically present.
• the six membered ring ofthe indole/azaindole nucleus can be unsubstituted or substituted.
• the six membered ring is unsubstituted or is substituted with up to two (for example one) small substituents selected from methyl, chlorine, amino, fluorine, nitro and acetamido.
• V is CH and/or W is CH or C-CH and/or U is selected from CH, C-CH 3 , and fluorine and/or T is a carbon atom substituted by methyl, chloro, nitro or a group (R 5 ) 2 N as hereinbefore defined
• both of U and W can be a group CR .
• V is CH.
• R 4 is a group R a -R b
• the moiety R a can be a chemical bond, or it can be O, S, SO, SO 2 , NH or N-C ⁇ hydrocarbyl
• the group R b can be C ⁇ - 8 hydrocarbyl optionally interrupted by O, S, SO, SO 2 , NH or N-C ⁇ - hydrocarbyl and optionally substituted by one or more substituents.
• hydrocarbyl groups and preferred hydrocarbyl groups are as set out above. In the context ofthe groups R a and R b , small alkyl groups are particularly preferred, for example methyl groups.
• Optional substituent groups for R are selected from hydroxy, amino, mono- or di- C ⁇ - 4 hydrocarbylamino, C M hydrocarbyloxy, oxo, C ⁇ - 4 hydrocarbylthio and halogen.
• Small substituent groups such as Ci groups and smaller halogens such as chlorine and fluorine are preferred.
• Each group R 5 in the optional group N(R 5 ) 2 is independently selected from hydrogen, C alkyl, C M acyl and C M alkylsulphonyl groups. Hydrogen and Ci groups are preferred.
• Each group R 6 when present, is independently selected from hydrogen and C hydrocarbyl, hydrogen and methyl being preferred.
• One particular subset of compounds ofthe formula (I) is the set of compounds having a substituent group Y which is a group -N(R 7 )-C(O)-R 8 or -N(R 7 )-SO 2 -R 8 .
• the group R 7 can be hydrogen, C hydrocarbyl or a group C(O)-R 8 or SO 2 -R 8 . Where it is C M hydrocarbyl, it is typically methyl.
• R 8 is selected from C ⁇ - ⁇ o hydrocarbyl, .io hydrocarbylamino, C ⁇ - ⁇ o hydrocarbylthio, Cno hydrocarbyloxy, and aryl, arylamino, arylthio and aryloxy groups, the terms hydrocarbyl and aryl being as generally defined above.
• the aryl moieties can be carbocyclic or heterocyclic and have from five to twelve ring members. Carbocyclic aryl groups such as phenyl, or monocyclic heterocyclic groups containing one or two nitrogen atoms, are presently preferred. Each substituent group R 8 can be unsubstituted or substituted by one or more groups R 4 as hereinbefore defined (other than Y).
• Y can take the form of an amide, carbamate, urea or thiourea compound.
• R 7 and R 8 together with the nitrogen and carbon or sulphur atoms to which they are attached can be linked to form a ring structure of 4 to 7 ring members.
• R 8 is an aryl, arylamino, arylthio or aryloxy group, it may be linked to R 7 to form a fused bicyclic heterocyclic structure.
• R 8 is selected from optionally substituted aryl, arylamino, arylthio and aryloxy, R 8 typically being a carbocyclic or heterocyclic aryl, arylamino, arylthio or aryloxy group wherein the aryl moiety has five or six ring members.
• R 8 is selected from unsubstituted aryl and arylamino groups, and substituted aryl and arylamino groups wherein the aryl group is phenyl or a five or six-membered heterocyclic group having one or two nitrogen ring members, for example a group selected from pyridyl, pyrazolyl and isoxazolyl groups.
• Particularly preferred aryl groups are phenyl, pyridyl (e.g.4-pyridyl) and pyrazolyl (e.g. 2- ⁇ yrazolyl).
• the aryl (e.g. phenyl, pyridyl or pyrazolyl) ring can be substituted by one or more substituents selected from halogen, a monocyclic heterocyclic group having up to seven ring members and a group R -R b .
• substituents are fluorine, chorine, methoxy, trifluoromethoxy, trifluoromethyl, methyl, ethyl, isopropyl, isobutyl, t-butyl, phenyl, and five and six membered monocyclic heterocyclic groups.
• the aryl group is a pyrimidinyl group, particularly a 2- pyrimidinyl group, it is preferred that the aryl group is not substituted by phenyl. Most preferably the aryl group is other than 5-phenylpyrimidin-2-yl.
• the aryl group is a phenyl ring containing one or two meta substituents, for example wherein one meta position on the phenyl ring is unsubstituted or is substituted by a group selected from fluorine, chorine, methoxy, trifluoromethoxy, trifluoromethyl, ethyl, methyl and isopropyl; and the other meta position is substituted by a group selected from fluorine, chorine, methoxy, trifluoromethoxy, trifluoromethyl, ethyl, methyl, isopropyl, isobutyl, t-butyl, phenyl, substituted phenyl, and five and six membered monocyclic heterocyclic groups.
• the phenyl ring contains a single substituent which is selected from m-trifluoromethyl and m-trifluoromefhoxy.
• the phenyl ring can bear a fluoro substituent at one met -position and a rnorpholino group at the other met ⁇ -position.
• the aryl ring is a pyridyl ring, such as a 4-pyridyl ring, substituted by a five or six membered monocyclic heterocyclic group such as rnorpholino.
• the aryl ring is a pyrazolyl or isoxazolyl (preferably pyrazolyl) group substituted by a phenyl group and/or a C M hydrocarbyl group, particularly a C ⁇ - 4 alkyl group, and most preferably a tertiary butyl group.
• a 2-phenyl-5-t-butylpyrazol-3-yl group has been found to be particularly advantageous.
• the five membered ring ofthe compounds ofthe formula (I) is linked via a linker group A to a heteroaryl group R 3 .
• the linker group has a linking chain length of one or two atoms: in other words the number of atoms in the backbone ofthe linker group is one or two.
• a group -CH 2 - has a linking chain length of one
• a group -CH 2 -CH 2 - has a linking chain length of two.
• Presently preferred linker groups A include CH 2 or CH 2 CH 2 , the ethylene group being particularly preferred.
• the heteroaryl group R is a monocyclic or bicyclic group containing from five to twelve ring members, and more usually from five to ten ring members.
• the hereoaryl group can be, for example, a five membered or six membered monocyclic ring or a bicyclic structure formed from fused five and six membered rings or two fused six membered rings.
• Each ring may contain up to about four heteroatoms, more usually three or fewer, and typically one, two or three.
• the heteroatoms are typically selected from nitrogen, sulphur and oxygen.
• the heteroaryl ring contains at least one ring nitrogen atom.
• the nitrogen atoms in the heteroaryl rings can be basic, as in the case of a pyridine or pyrimidine, or essentially non-basic as in the case of an indole or pyrrole nitrogen.
• the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents ofthe ring, will be less than five.
• heteroaryl groups R 3 include but are not limited to pyridyl, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, pyrazinyl, pyrimidinyl, triazinyl, quinolinyl, isoquinolinyl, tetrazolyl, benzfuranyl, chromanyl, tliiochromanyl, benzimidazolyl, benzoxazolyl, benzisoxazole, benzthiazolyl and benzisothiazole, isobenzofuranyl, isoindolyl, indolizinyl, indolinyl, isoindolinyl, purinyl (e.g., adenine, guanine), indazo
• the group R 3 is a monocyclic heteroaryl group containing at least one nitrogen atom, and one particular example of such a group is pyridyl, for example a 4-pyridyl group.
• the group R can be unsubstituted or substituted by one or more groups selected from halogen, nitro, cyano, a monocyclic heterocyclic group having up to seven ring members, a group N(R 5 ) 2 , a group C(O)N(R 6 ) , a group SO 2 N(R 6 ) 2 , and a group R a -R b ; wherem R 5 , R 6 , R a and R b are as hereinbefore defined.
• R 3 is unsubstituted.
• R is substituted.
• substituents include but are not limited to CM alkyl, Ci- 6 alkoxy, amino, C ⁇ . 6 alkylamino, di-d- alkylamino, halogen, hydroxy, trifluoromethyl, cyano, nitro, C 2 .
• substituents include chlorine, fluorine, methyl, unsubstituted amino, 2-hydroxyethylamino, 2-hydroxyprop-2-ylamino, 2- hydroxy-2-methylprop-2-ylamino, 1-phenylethyl, rnorpholino and piperazino groups.
• substituents each having a chain length of greater than three atoms are present on the heteroaryl group R 3 , it is preferred that they are located on the "same side" ofthe ring. In other words, where for example three such larger substituents are present on a six membered ring, it is preferred that they are located at adjacent ortho, meta and para positions, relative to the point of attachment to the group A. Where two such larger substituents are present, it is preferred that they are located on adjacent ortho and meta positions, or adjacent meta and para positions, or adjacent (spaced apart by one ring position) ortho and para positions.
• chain length in the present context refers to the number of atoms extending in a continuous chain outwardly from the heteroaryl ring.
• a chlorine substituent has a chain length of one
• a methyl group has a chain length of two
• an ethyl group has a chain length of three.
• “Smaller substituents”, i.e. substituents having a chain length of three or less, may be present on one or both "sides" ofthe ring, whether or not "larger" substituents are also present.
• the group -A-R contains no carboxylic, phosphonic and sulphonic acid groups, nor any tetrazole or -C(O)NSO 2 - groups.
• U, T, V and W are all CH
• R 1 and R 2 are bbootthh hhyyddrrooggeenn
• a ani d R° is a group -CH 2 -CH 2 -R3
• R 3 is other than a pyrazin-3-yl or pyrid-3-yl group.
• the group -A-R 3 can be attached to either the 1 -position or the 3 -position ofthe five membered ring, preferably the 3 -position.
• R° is -A-R 3
• R 1 is hydrogen or methyl, particularly hydrogen.
• R° is hydrogen or methyl, particularly hydrogen.
• the group Y is advantageously located at the 5-position ofthe bicyclic (e.g. indole) group.
• the group Y is advantageously located at the 6-position ofthe bicyclic (e.g. indole) group.
• R 2 is typically a small substituent and preferably is selected from hydrogen and methyl. Most typically, R is hydrogen.
• the invention provides novel compounds per se ofthe formula (I).
• One group of novel compounds within the scope ofthe present invention is the group of compounds ofthe formula (I) as hereinbefore defined but provided that one group R 4 is a group Y, and excluding the known compound wherein in combination R 1 and R 2 are hydrogen, U, V and W are all CH and T is a carbon atom bearing an unsubstituted benzamido group.
• the group -A-R 3 contains no carboxylic, phosphonic and sulphonic acid groups, nor any tetrazole or -C(O)NSO 2 - groups. It is also preferred that when -A- is -C(O)N-, the nitrogen atom ofthe group A is not linked directly to a furan or thiophene ring. It is further preferred, in respect ofthe novel compounds ofthe formula (I), that R is H or methyl.
• One sub-group of novel compounds is the group of compounds ofthe formula (I) wherein either T or N (preferably T) is a group C-Y, wherein Y is a group - ⁇ (R 7 )- C(O)-R 8 or -N(R 7 )-SO 2 -R 8 as hereinbefore defined.
• R is selected from carbocyclic or heterocyclic aryl, arylamino, arylthio and aryloxy groups wherein the aryl moiety has five or six ring members (but excluding the known unsubstituted benzamido compound referred to above) and R 7 is hydrogen or - 4 hydrocarbyl (preferably hydrogen or methyl).
• One group of preferred novel compounds per se is the group in which the aryl moiety is carbocyclic, for example wherein R 8 is selected from unsubstituted phenyl and phenylamino groups, and substituted phenyl and phenylamino groups.
• the aryl moiety is a five or six membered heterocylic group having one or two nitrogen ring members, for example a pyridyl or pyrazolyl group.
• Particular novel compounds ofthe invention are compounds wherein the phenyl, pyridyl or pyrazolyl ring is substituted by one or more substituents selected from halogen, a monocyclic heterocyclic group having up to seven ring members and a group R a -R b as hereinbefore defined.
• substituents are selected from fluorine, chorine, methoxy, trifluoromethoxy, trifluoromethyl, methyl, ethyl, isopropyl, isobutyl, t-butyl,' phenyl, and five and six membered monocyclic heterocyclic groups.
• One sub-group of compounds per se is the group of compounds wherein the phenyl ring contains one or two meta substituents, for example wherein one meta position on the phenyl ring is unsubstituted or is substituted by a group selected from fluorine, chorine, methoxy, trifluoromethoxy, trifluoromethyl, ethyl, methyl and isopropyl; and the other met ⁇ position is substituted by a group selected from fluorine, chorine, methoxy, trifluoromethoxy, trifluoromethyl, ethyl, methyl, isopropyl, isobutyl, t-butyl, phenyl, substituted phenyl, and five and six membered monocyclic heterocyclic groups.
• Examples of particularly preferred novel compounds ofthe invention are those wherein the phenyl ring contains a single substituent which is selected from m- trifluoromethyl and m-trifluoromethoxy groups.
• aryl ring is a pyrazolyl ring substituted by a phenyl group and a tert-butyl group.
• the compound is an indole in which R° is - A-R 3 , wherein A is ethylene and R 3 is a pyrimidinyl group substituted at the 2- position by a hydroxyalkylamino group or a phenylethyl group.
• novel compounds within the scope ofthe present invention include: 3-(2-(4-pyridyl)ethyl)-5-(3-trifluoromethoxybenzamido)indole;
• the invention provides novel compounds ofthe formula (I) as hereinbefore defined for use in medicine and pharmaceutical compositions comprising a novel compound ofthe formula (I) in association with a pharmaceutically acceptable carrier.
• Acid addition salts may be formed with a wide variety of acids, both inorganic and organic.
• acid addition salts include salts formed with hydrochloric, hydriodic, phosphoric, nitric, sulphuric, citric, lactic, succinic, maleic, malic, isethionic, fumaric, benzenesulphonic, toluenesulphonic, methanesulphonic, ethanesulphonic, naphthalenesulphonic, valeric, acetic, propanoic, butanoic, malonic, glucuronic and lactobionic acids.
• formula (I) Also encompassed by formula (I) are any polymorphic forms ofthe compounds, solvates (e.g. hydrates), complexes (e.g. inclusion complexes or clathrates with compounds such as cyclodextrins, or complexes with metals) ofthe compounds, and pro-drugs ofthe compounds.
• prodrugs is meant for example any compound that is converted in vivo into a biologically active compound ofthe formula (I). Where the compounds ofthe formula (I) contain chiral centres, all individual optical forms such as enantiomers, epimers and diastereoeisomers, as well as racemic mixtures ofthe compounds are within the scope of formula (I).
• Compounds of the formula (I) can be prepared in accordance with methods known per se or as described herein.
• compounds ofthe formula (I) wherein the group A-R 3 is attached to the 3-position ofthe five membered ring can be prepared in accordance with methods similar or analogous to those described in US patent numbers US 3,300,506 and US 3,409,626, the disclosures of each of which are incorporated herein by reference.
• compounds ofthe formula (I) bearing a group A-R 3 at the 3-position ofthe five membered ring can be prepared by reacting a compound ofthe formula (II):
• Compounds ofthe formula (I) in which the linker group is CH, CR, C(O), S(O), S(O 2 ) or C(O)CH and is attached to the 3-position ofthe five membered ring can be prepared by electrophilic substitution, for example by means of a Friedel Crafts- type reaction, of a compound ofthe formula (II) as defined above.
• Reagents for effecting electrophilic substitution can take the form R 3 -A'-X wherein X is a suitable leaving group such as a halogen (e.g. chlorine) and A' is selected from CH, CR, C(O), S(O), S(O 2 ) and C(O)CH 2 .
• Alkylation at the 3-position can also be carried out by reacting an appropriately substituted 3 -unsubstituted indole compound ofthe formula R 3 -A'-X wherein A' is methylene or ethylene and X is a leaving group such as bromine in the presence of silver (I) oxide in a polar solvent such as dioxan, under conditions similar or analogous to those described in WO99/43654.
• Compounds ofthe formula (I) in which the linker group is -CO- can be prepared by formation of 3-indole organometallic reagents (e.g. Grignard) from the corresponding 3-halogen substituted indole (e.g. iodine) and then treatment with the appropriate R heterocycle acid chloride under conditions similar or analogous to those described in Indian J. Chem., 24 B(10), 1012-14, 1985. Indole-3 -halogens can be obtained from commercial sources or can be prepared by known methods.
• 3-indole organometallic reagents e.g. Grignard
• 3-halogen substituted indole e.g. iodine
• Indole-3 -halogens can be obtained from commercial sources or can be prepared by known methods.
• Compounds ofthe formula (I) in which the linker group is -CH 2 CO- can be prepared by reacting a suitably N-l protected derivative of an indole or azaindole acetic acid ester with a strong base in the presence ofthe appropriately substituted heterocyclic ester (e.g. methyl 4-pyridyl carboxylate), followed by hydrolysis and decarboxylation under conditions similar or analogous to those described in Khim. Geterotsikl. Soedin., (1), 55-58, 1980.
• Indole carboxylic acids can be obtained from commercial sources (for example indole-3 -acetic acid) or can be prepared by known methods. Indole or azaindole carboxylic acids or their reactive derivatives can also be used to prepare compounds in which the linker group is CONH by reaction with an appropriate amino substituted heterocyclic group R 3 .
• the ester group can thereafter be reduced to a methyl group to give a compound ofthe formula (I) wherein R 2 is methyl or hydrolysed to the carboxylic acid and removed by decarboxylation to give a compound ofthe formula (I) wherein R 2 is hydrogen.
• Indoles bearing a CH 2 NMe 2 group at the 3-position can be prepared from the corresponding 3-formyl compound by a standard reductive alkylation using, for example, dimethylamine and sodium cyanoborohydride.
• an appropriately substituted indole 3- carboxylic acid methyl or ethyl ester can be subjected to a hydride reduction to give the 3-hydroxymethyl derivative and then converted to the dimethylamino group in known fashion.
• 3-haloindole e.g. a 3-bromoindole
• a metal hydride reducing agent such as lithium aluminium hydride
• an N-protected indole or aza-indole bearing a 3 -CHO group can be reacted under Wittig-type conditions with a triphenyl(arylmethyl)phosphonium compound suitable for introducing the group R .
• the N-protecting group can be, for example, a phenylsulphonyl group.
• Such reactions are typically carried out under anhydrous conditions at low temperature in a polar non-protic solvent such as tetrahydrofuran.
• linker group A is SO 2 CH 2 or SOCH 2
• a sulphonylating agent such as R 3 CH 2 SO 2 Cl.
• linker group A is SO 2 NR
• compounds wherein the linker group A is SO 2 NR can be prepared by reacting 3- indolylsulphonyl chlorides with an amine ofthe formula R 3 NH 2 or R 3 NH 2 Me, optionally in the presence of another base, for example under conditions similar or analogous to those described in Buyanov et al, Khim. Geterotsikl. Soedin (1996), (1), 40-42 or as described in WO00/73264.
• linker group A is NHSO 2
• a suitably 1 -protected 3- unsubstituted indole for example in a polar solvent such as dimethylsulphoxide (DMSO), under conditions similar or analogous to those described in J Chem. Soc, Perkin Transactions 1, (8), 1688-92; 1980.
• DMSO dimethylsulphoxide
• compounds wherein the linker group A is NHSO 2 can be prepared by reacting a 3 -amino indole with R 3 SO 2 Cl, for example under conditions similar or analogous to those described in Khim. Geterotsikl. Soedin., (4), 481-5; 1977.
• linker group A is NRCH 2
• compounds wherein the linker A is a group is NRCH 2 can be prepared by reduction of a compound wherein A is NHCO with a metal hydride reducing agent such as LiAlH 4 .
• compounds wherein the linker group A is NHCO can be prepared from a 3 -amino 2- ethoxycarbonyl indole, for example under conditions similar or analogous to those described in J Heterocycl. Chem., 24(2), 437-9; 1987, followed by reduction ofthe ester group to give the 2-methyl compound or hydrolysis and decarboxylation to give the 2-unsubstituted compound.
• Linker group A is S
• Compounds wherein the linker group A is S can be prepared by reaction of a aryl substituted hydrazine ofthe formula ArNHNH 2 , wherein Ar is a substituted or unsubstituted phenyl group, with a compound ofthe formula R 2 -C(O)-CH 2 -S-R 3 to form a hydrazone and then cyclising the hydrazone in the presence of an acid such as acetic acid to give the desired compound.
• the reaction can be carried out under conditions similar or analogous to those described in Synthesis, (3), 270-2; 1994.
• Compounds ofthe formula (I) containing a group CR 4 wherein R 4 is a substituted amino group can be prepared from the corresponding amino-indole or amino-aza- indole compounds.
• the amino group when the amino group is substituted by an acyl group such as a benzoyl or substituted benzoyl group, the compound can be prepared by acylation ofthe corresponding amino compound.
• Such acylation reactions can be conducted in a polar solvent (such as dimethyl formamide or dimethylsulphoxide) in the presence of an acylation catalyst such as hydroxybenzotriazole, typically at a non-extreme temperature such as room temperature.
• the acylation ofthe amino group on the six membered ring ofthe fused ring system can be carried out before or after introducing the group R .
• the carbamoyl group can be introduced by reacting the corresponding amino analogue with an isocyanate such as an optionally substituted phenyl isocyanate. Reaction with an isocyanate can be carried out in a solvent, for example a chlorinated solvent such as chloroform or dichloromethane, at a moderately elevated temperature, for example between 60°C and 100°C.
• a solvent for example a chlorinated solvent such as chloroform or dichloromethane
• Compounds wherein the group R 4 is an amino group can be prepared by reduction ofthe corresponding nitro-substituted compound.
• the reducing agent will generally be chosen so that it brings about reduction of the nitro group but not any heterocyclic group R 3 that may be present.
• An example of a suitable reducing agent is an Fe/Fe(II) mixture which can be employed in a suitable polar solvent such as a dioxane, at a moderately elevated temperature between 60°C and 100°C (for example at around 90°C).
• Compounds having a substituent A-R 3 at the 1- position can also be prepared by reacting a 1-N-unsubstituted compound with a compound L-A-R 3 , where L is a leaving group (such as a halide), in the presence of a strong base such as an alkali metal, an alkali metal hydride or hydroxide or an organometallic reagent such as an alkyl lithium.
• the indole 1 -position is protected in order to prevent it from taking part in the reaction.
• the protecting group used can be a simple alkyl group such as methyl, thereby leading directly to a compound ofthe formula (I) wherein R 1 is alkyl.
• the protecting group may be a removable protecting group such as an acyl group, a phenylsulphonyl group or a trialkylsilyl group such as tri- isopropylsilyl.
• Such protecting groups can be removed at an appropriate point in the reaction sequence by methods well known er se, for example using fluoride ion in the case of a silyl protecting group. Examples of protecting groups are described in the references set out above, and also in, for example, Protective Groups in Organic Synthesis (T. Green and P. Wuts; 3rd Edition; John Wiley and Sons, 1999).
• novel intermediates are the compounds corresponding to the preferred novel compounds per se as hereinbefore defined, but lacking the -A-R 3 group.
• the invention also provides compounds ofthe formula (I) as hereinbefore defined in the form of pharmaceutical compositions.
• compositions can be in any form suitable for oral, parenteral, topical, intranasal, intra-articular, ophthalmic, otic, rectal, intra-vaginal, or transdermal administration, or administration by inhalation.
• compositions are intended for parenteral administration, they can be formulated for intravenous, intramuscular or subcutaneous administration.
• compositions containing compounds ofthe formula (I) can be formulated in accordance with known teclmiques, see for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, USA.
• tablet compositions can contain a unit dosage of active compound together with an inert diluent or carrier such as a sugar or sugar alcohol, eg; lactose, sucrose, sorbitol or mannitol; and/or a non-sugar derived diluent such as sodium carbonate, calcium phosphate, calcium carbonate, or a celluloses or derivative thereof such as methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, and starches such as corn starch. Tablets may also contain such standard ingredients as binding and granulating agents agents such as polyvinylpyrrolidone, disintegrants (e.g.
• swellable crosslinked polymers such as crosslinked carboxymethylcellulose
• lubricating agents e.g. stearates
• preservatives e.g. parabens
• antioxidants e.g. BHT
• buffering agents for example phosphate or citrate buffers
• effervescent agents such as citrate/bicarbonate mixtures.
• Capsule formulations may be ofthe hard gelatin or soft gelatin variety and can contain the active component in solid, semi-solid, or liquid form.
• Gelatin capsules can be formed from animal gelatin or synthetic or plant derived equivalents thereof.
• the solid dosage forms can be coated or un-coated, but typically have a coating, for example a protective film coating (e.g. a wax or varnish) or a release controlling coating.
• a protective film coating e.g. a wax or varnish
• the coating e.g. a Eudragit TM type polymer
• the coating can be designed to release the active component at a desired location within the gastro-intestinal tract.
• the coating can be selected so as to degrade under certain pH conditions within the gastrointestinal tract, thereby selectively release the compound in the stomach or in the ileum or duodenum.
• the drug can be presented in a solid matrix comprising a release controlling agent, for example a release delaying agent which may be adapted to selectively release the compound under conditions of varying acidity or alkalinity in the gastrointestinal tract.
• a release controlling agent for example a release delaying agent which may be adapted to selectively release the compound under conditions of varying acidity or alkalinity in the gastrointestinal tract.
• the matrix material or release retarding coating can take the form of an erodible polymer (e.g. a maleic anhydride polymer) which is substantially continuously eroded as the dosage form passes through the gastrointestinal tract.
• compositions for topical use include ointments, creams, sprays, patches, gels, liquid drops and inserts (for example intraocular inserts). Such compositions can be formulated in accordance with known methods.
• compositions for parenteral and intra-articular administration are typically presented as sterile aqueous or oily solutions or fine suspensions, or may be provided in finely divided sterile powder form for making up extemporaneously with sterile water for injection.
• formulations for rectal or intra-vaginal administration include pessaries and suppositories which may be, for example, formed from a shaped moldable or waxy material containing the active compound.
• compositions for administration by inhalation may take the form of inhalable powder compositions or liquid or powder sprays, and can be administrated in standard form using powder inhaler devices or aerosol dispensing devices. Such devices are well known.
• the powdered formulations typically comprise the active compound together with an inert solid powdered diluent such as lactose.
• a formulation intended for oral administration may contain from 0.1 milligrams to 2 grams of active ingredient, more usually from 10 milligrams to 1 gram, for example, 50 milligrams to 500 milligrams.
• the active compound will be administered to a patient in need thereof (for example a human or animal patient) in an amount sufficient to achieve the desired therapeutic effect.
• the compounds ofthe formula (I) will useful in the prophylaxis or treatment of a range of disease states or conditions mediated by p38 MAP kinases. Examples of such disease states and conditions are set out above.
• Compounds ofthe formula (I) are generally administered to a subject in need of such administration, for example a human or animal patient, preferably a human.
• the compounds will typically be administered in amounts that are therapeutically or prophylactically useful and which generally are non-toxic.
• the benefits of administering a compound ofthe formula (I) may outweigh the disadvantages of any toxic effects or side effects, in which case it may be considered desirable to administer compounds in amounts that are associated with a degree of toxicity.
• a typical daily dose ofthe compound can be in the range from 100 picograms to 10 milligrams per kilogram of body weight, more typically 10 nanograms to 1 milligram per kilogram of bodyweight although higher or lower doses may be administered where required.
• the quantity of compound administered will be commensurate with the nature ofthe disease or physiological condition being treated and will be at the discretion ofthe physician.
• the compounds ofthe formula (I) can be administered as the sole therapeutic agent or they can be administered in combination therapy with one of more other compounds for treatment of a particular disease state, for example rheumatoid arthritis and osteoarthritis.
• other therapeutic agents that may be administered together (whether concurrently or at different time intervals) with the compounds ofthe formula (I) include methotrexate, prednisilone, sulfasalazine, leflunomide and NSAIDs, for example COX-2 inhibitors such as celecoxib and rofecoxib.
• Example 1 By substituting the appropriate vinyl substituted monoheterocycle for vinyl pyridine and using the appropriate indole or azaindole, the method of Example 1 was used to prepare the following compounds.
• the activated p38 was then diluted six-fold with assay buffer, and lO ⁇ l mixed with lO ⁇ l of MBP mix (150 ⁇ l lOx strength assay buffer (250mM HEPES pH 7.4, 250mM ⁇ -glycerophosphate, 50mM EDTA, 150mM MgCl 2 ), 1.5 ⁇ M of lOmM DDT and lOmM sodium orthovanadate, 7.5 ⁇ M of lOmM ATP, 723 ⁇ M water, 35 ⁇ Ci ⁇ 33 P-ATP, lOO ⁇ l myelin basic protein (MBP) (5mg/ml)) and added to 96 well plates along with 5 ⁇ l of various dilutions ofthe test compound in DMSO (up to 10%).
• MBP mix 150 ⁇ l lOx strength assay buffer (250mM HEPES pH 7.4, 250mM ⁇ -glycerophosphate, 50mM EDTA, 150mM MgCl 2 )
• THP-1 cells human monocytic leukaemic cell line, ECACC
• culture medium [RPMI 1640 (Invitrogen) and 2mM L-Glutamine supplemented with 10% foetal bovine serum (Invitrogen)] at approximately 37°C in humidified 5% CO 2 in stationary culture.
• THP-1 cells were suspended in culture medium containing 50ng/ml PMA (SIGMA), seeded into a 96-well tissue culture plate (IWAKI) at 1 x 10 5 cells/well (lOO ⁇ l/well) and incubated as described above for approximately 48h. The medium was then aspirated, the wells washed twice in Phosphate Buffered Saline and 1 ⁇ g/ml LPS (SIGMA) in culture medium was added (200 ⁇ l/well).
• SIGMA 96-well tissue culture plate
• Test compounds were reconstituted in DMSO (SIGMA) and then diluted with the culture medium such that the final DMSO concentration was 0.1 %. Twenty microlitre aliquots of test solution or medium only with DMSO (solvent control) were added to triplicate wells immediately following LPS addition, and incubated for 6h as described above. Culture supernatants were collected and the amount of human TNF- ⁇ present was determined by ELISA (R&D Systems) performed according to the manufacturer's instructions.
• the IC 5 o was defined as the concentration ofthe test compound corresponding to half maximal inhibition ofthe control activity by non-linear regression analysis of their inhibition curves.
• the IC50 for the compound of 14B (5 -(3 -Fluoro-5 -(4- morpholino)benzamido)-3-(2-(4-pyridyl)ethyl)indole) was found to be 530nM.
• a tablet composition containing a compound ofthe formula (I) is prepared by mixing 50mg ofthe compound with 197mg of lactose (BP) as diluent, and 3mg magnesium stearate as a lubricant and compressing to form a tablet in known manner.
• BP lactose
• a capsule formulation is prepared by mixing lOOmg of a compound ofthe formula (I) with lOOmg lactose and filling the resulting mixture into standard opaque hard gelatin capsules.

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