EP1805132A2 - Nouveaux composes - Google Patents

Nouveaux composes

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Publication number
EP1805132A2
EP1805132A2 EP05857821A EP05857821A EP1805132A2 EP 1805132 A2 EP1805132 A2 EP 1805132A2 EP 05857821 A EP05857821 A EP 05857821A EP 05857821 A EP05857821 A EP 05857821A EP 1805132 A2 EP1805132 A2 EP 1805132A2
Authority
EP
European Patent Office
Prior art keywords
optionally substituted
methyl
hydrogen
groups
mmol
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP05857821A
Other languages
German (de)
English (en)
Other versions
EP1805132A4 (fr
Inventor
Jeffrey C. Boehm
James Francis Callahan
Zehong Wan
Hongxing Yan
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
GlaxoSmithKline LLC
Original Assignee
SmithKline Beecham Corp
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Filing date
Publication date
Application filed by SmithKline Beecham Corp filed Critical SmithKline Beecham Corp
Publication of EP1805132A2 publication Critical patent/EP1805132A2/fr
Publication of EP1805132A4 publication Critical patent/EP1805132A4/fr
Withdrawn legal-status Critical Current

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    • C07C233/69—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom of an acyclic saturated carbon skeleton
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Definitions

  • This invention relates to novel compounds and their use as pharmaceuticals, particularly as p38 kinase inhibitors, for the treatment of certain diseases and conditions.
  • Intracellular signal transduction is the means by which cells respond to extracellular stimuli. Regardless of the nature of the cell surface receptor (e. g. protein tyrosine kinase or seven-transmembrane G-protein coupled), protein kinases and phosphatases along with phospholipases are the essential machinery by which the signal is further transmitted within the cell [Marshall, J. C. Cell , 80, 179-278 (1995)].
  • the cell surface receptor e. g. protein tyrosine kinase or seven-transmembrane G-protein coupled
  • protein kinases and phosphatases along with phospholipases are the essential machinery by which the signal is further transmitted within the cell [Marshall, J. C. Cell , 80, 179-278 (1995)].
  • Protein kinases can be categorized into five classes with the two major classes being tyrosine kinases and serine / threonine kinases, depending upon whether the enzyme phosphorylates its substrate(s) on specific tyrosine(s) or serine / threonine(s) residues [Hunter, T., Methods in Enzymoloqy (Protein Kinase Classification) p. 3, Hunter, T.; Sefton, B. M.; eds. vol. 200, Academic Press; San Diego, 1991].
  • the mitogen-activated kinases are now understood to transduce signals from many extracellular stimuli such as environmental stress, infectious agents, cytokines and growth factors.
  • the MAPKs modulate the activity of numerous cell functions such as translocation and activation of transcription factors that control transcription of effector molecules such as cytokines, COX-2, iNOS; the activity of downstream kinases that effect translation of mRNAs; and cell cycle pathways through transcription or modification of enzymes.
  • One of these three major pathways is the p38 MAPK pathway, which refers in most cell types to the isoform p38a which is ubiquitously expressed.
  • Extracellular stimuli such as those described above are generated in a number of chronic diseases which are now understood to have a common underlying pathophysiology termed inflammation.
  • An environmental insult or local cell damage activates cellular response pathways, including but not limited to p38; local cells then generate cytokines and chemokines, in turn recruiting lymphocytes such as neutrophils and other granulocytes.
  • lymphocytes such as neutrophils and other granulocytes.
  • the consequences include recruitment of additional lymphocytes such as additional phagocytic cells or cytotoxic T cells, and ultimately the adaptive immune response is initiated through activation of T cells.
  • Atherosclerosis is regarded as a chronic inflammatory disease, which develops in response to injury of the vessel wall and is characterized by the complex development of an occlusive and prothrombotic atheroma.
  • the pathogenesis of this lesion generally involves endothelial dysfunction (reduced bioavailable NO), adhesion molecule expression, adhesion and infiltration of leukocytes, cytokine and growth factor generation, accumulation of foam cells, expansion of extracellular lipid and matrix, activation of matrix metalloproteases (MMPs) and proliferation of vascular smooth muscle cells.
  • endothelial dysfunction reduced bioavailable NO
  • adhesion molecule expression adhesion and infiltration of leukocytes
  • cytokine and growth factor generation accumulation of foam cells
  • expansion of extracellular lipid and matrix activation of matrix metalloproteases (MMPs) and proliferation of vascular smooth muscle cells.
  • MMPs matrix metalloproteases
  • CSBP CSBP
  • p38 the isoforms p38 ⁇ and p38 ⁇ are the targets of the compounds described
  • SK&F 86002 was the prototypic example.
  • These compounds inhibited IL-1 and TNF synthesis in human monocytes at concentrations in the low uM range [Lee, et al., Int. J. Immunopharmac. 10(7), 835(1988)] and exhibited activity in animal models which are refractory to cyclooxygenase inhibitors [Lee; et al., Annals N. Y. Acad. ScL 696, 149(1993)].
  • the mechanism by which stress signals (including bacterial and viral infection, pro-inflammatory cytokines, oxidants, UV light and osmotic stress) activate p38 is through activation of kinases upstream from p38 which in turn phosphorylate p38 at threonine 180 and tyrosine 182 resulting in p38 activation.
  • MAPKAP kinase-2 and MAPKAP kinase-3 have been identified as downstream substrates of CSBP/p38 which in turn phosphorylate heat shock protein Hsp27 and other substrates. Additional downstream substrates known to be phosphorylated by p38 include kinases (Mnk1/2, MSK1/2 and PRAK) and transcription factors (CHOP, MEF2, ATF2 and CREB).
  • p38 kinase inhibitors are effective in a number of different cell types in decreasing the synthesis of a wide variety of pro-inflammatory proteins including, IL-6, IL-8, GM-CSF, RANTES and COX-2.
  • Inhibitors of p38 kinase have also been shown to suppress the TNF-induced expression of VCAM-1 on endothelial cells, the TNF-induced phosphorylation and activation of cytosolic PLA2 and the IL-1 -stimulated synthesis of collagenase and stromelysin.
  • IL-1 lnterleukin-1
  • TNF Tumor Necrosis Factor
  • IL-1 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.
  • T helper cells the activation of T helper cells
  • induction of fever the stimulation of prostaglandin or collagenase production
  • neutrophil chemotaxis the stimulation of acute phase proteins
  • acute phase proteins the suppression of plasma iron levels.
  • IL-1 production There are many disease states in which excessive or unregulated IL-1 production is implicated in exacerbating and/or causing the disease.
  • rheumatoid arthritis include 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, muscle degeneration, cachexia, psoriatic arthritis, Reiter's syndrome, rheumatoid arthritis, gout, traumatic arthritis, rubella arthritis, and acute synovitis.
  • Evidence also links IL-1 activity to diabetes and pancreatic ⁇ cells [review of the biological activities which have been attributed to IL-1 Dinarello, J. Clinical Immunology, 5 (5), 287-297 (1985)].
  • TNF production has been implicated in mediating or exacerbating a number of diseases including rheumatoid arthritis, 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 obstructive pulmonary disease, silicosis, pulmonary sarcoisosis, bone resorption diseases, reperfusion injury, graft vs.
  • diseases including rheumatoid arthritis, 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 obstructive pulmonary disease, silicosis, pulmonary sarcoisosis, bone
  • allograft rejections fever and myalgias due to infection, such as influenza, 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, or pyresis.
  • AIDS 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 Crohn's disease
  • ulcerative colitis or pyresis.
  • CRP C- reactive protein
  • IL-6 stimulation of CRP production is directly inhibited by p38 inhibitors in human vascular endothelial cells, and CRP is produced by hepatocytes in response to IL-6.
  • CRP is considered a major risk factor for cardiovascular disease [Circulation 2003.107: 363-369] and may be a significant independent risk factor for chronic obstructive pulmonary disease [Circulation 2003. 107:1514-1519].
  • IL- 6 is also upregulated in endometriosis [Bedaiwy et al., 2002, Human
  • lnterleukin-8 (IL-8) and RANTES are chemotactic factors produced by several cell types including mononuclear cells, fibroblasts, endothelial cells, epithelial cells, neutrophils and T cells. Chemokine production is induced by pro- inflammatory stimuli such as IL-1 , TNF, or lipopolysachharide (LPS), or viral infection. IL-8 stimulates a number of functions in vitro. It has been shown to have chemoattractant properties for neutrophils, T-lymphocytes, and basophils.
  • IL-8 has also been shown to increase the surface expression of Mac-1 (CD11 b/CD18) on neutrophils without de novo protein synthesis, which may contribute to increased adhesion of the neutrophils to vascular endothelial cells.
  • Mac-1 CD11 b/CD18
  • Many diseases are characterized by massive neutrophil infiltration.
  • Conditions such as chronic obstructive pulmonary disease associated with an increase in IL-8 production would benefit by compounds which are suppressive of IL-8 production.
  • RANTES is produced by cells such as epithelial cells and airway smooth muscle in response to infection or cytokine stimulation. Its main chemoattraction is for T cell subtypes and blood-borne monocytes.
  • IL-1 , TNF and other cytokines affect a wide variety of cells and tissues and these cytokines as well as other leukocyte derived cytokines are important as 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.
  • CSBP/p38 signal transduction via CSBP/p38 is required for the effector functions of several of these same pro-inflammatory proteins plus many others.
  • growth factors such as VEGF, PDGF, NGF signal through surface receptors which in turn activate cellular signaling pathways including p38 MAPK [Ono, K. and Han, J., Cellular Signalling, 12 1 -13 (2000); Kyriakis, JM and Avruch, J. Physiol Rev 81 : 807-869 (2001)].
  • TGF ⁇ a key molecule in the control of inflammatory response, also activates p38 as a consequence of engagement of the TGF ⁇ receptor.
  • the involvement of CSBP/p38 in multiple stress-induced signal transduction pathways provides additional rationale for the potential utility of CSBP/p38 in the treatment of diseases resulting from the excessive and destructive activation of the immune system, or chronic inflammation. This expectation is supported by the potent and diverse activities described for CSBP/p38 kinase inhibitors [Badger, et al., J. Pharm. Exp. Thera. 279 (3): 1453- 1461.(1996); Griswold, et al, Pharmacol. Comm. 7. 323-229 (1996); Jackson, et al., J. Pharmacol.
  • TGF- ⁇ transforming growth factor beta
  • TGF- ⁇ increases the kinase activity of p38 MAPK through the TGF- ⁇ activated kinase TAK-1 (Hanafusa et al., 1999, J. Biol. Chem. 274:27161 -27167).
  • the p38 inhibitor SB- 242235 inhibited the TGF- ⁇ -induced increases in fibronectin and thrombospondin (Laping et al., 2002, Molec. Pharmacol. 62:58-64).
  • P38 also plays a role in directing survival and apoptosis of cells in response to various stimuli. Both survival and apoptosis can be p38 regulated depending on the stimulus and the cell type [Morin and Huot, Cancer Research. 64:1893-1898 (2004)].
  • TGF-beta can stimulate apoptosis in murine hepatocytes through activation of gadd45b, a protein involved in cell-cycle control, in a p38 mediated process [Yoo et al, J. Biol. Chem. 278:43001 -43007, (2003)].
  • UV-stress can activate p38 and trigger apoptosis of a damaged cell.
  • P38 has also been shown to promote survival of lymphocytes in response to stress, including neutrophils and CD8+ T cells.
  • the present invention is directed to such novel compounds which are inhibitors of p38 kinase.
  • This invention relates to the novel compounds of Formula (I), and pharmaceutical compositions comprising a compound of Formula (I), and a pharmaceutically acceptable diluent or carrier.
  • This invention relates to a method of treating a CSBP/RK/p38 kinase mediated disease in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound of Formula (I).
  • This invention relates to a method of inflammation in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound of Formula (I).
  • This invention also relates to a method of inhibiting cytokines and the treatment of a cytokine mediated disease, and the inflammation associated therewith, in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound of Formula (I).
  • This invention more specifically relates to a method of inhibiting the production of IL-1 , IL-8, or TNF in a mammal in need thereof which comprises administering to said mammal an effective amount of a compound of Formula (I). Accordingly, the present invention provides for a compound of the formula:
  • R 1 is selected from hydrogen, Ci ⁇ alkyl optionally substituted by up to three groups independently selected from C-i- ⁇ alkoxy, halogen and hydroxy, C3-7cycloalkyl optionally substituted independently by one or more C-i- ⁇ alkyl groups, an aryl, heteroaryl, or heterocyclic ring, all optionally substituted, independently, by up to three groups selected from R ⁇ and R ⁇ ;
  • R 2 is selected from hydrogen, Ci_galkyl or a -(CH2)p-C3_7cycloalkyl optionally substituted independently by one or more C-
  • R 3 is halogen or methyl;
  • R 4 is hydrogen, C1 -6 alkyl, halo-substituted-C-1 -4 alkyl, or C-3-7cycloalkyl;
  • R 5 is selected from C-
  • R6 j s selected from hydrogen, C-j. ⁇ alkyl, OR 4 , halogen, trifluoromethyl and -(CH 2 ) q NR 1 1 R 12 ;
  • R 8 is selected from hydrogen, Ci- ⁇ alkyl, C3.7Cycloalkyl optionally substituted by one or more C- ⁇ alkyl groups, OH, C-i-galkyl optionally substituted by one or more hydroxyl groups, CONHR 9 , phenyl optionally substituted by R 13 and/or R 14 , or a heteroaryl optionally substituted by R 13 and/or R 14 ;
  • R 9 and R 10 are each independently selected from hydrogen and C-
  • R 9 and R 10 together with the nitrogen atom to which they are bound, form a five- to six-membered heterocyclic ring optionally containing one additional heteroatom selected from oxygen, sulfur and N-R 1 ⁇ 1 wherein the ring is optionally substituted by up to two Ci ⁇ alkyl groups;
  • R 1 1 is selected from hydrogen, C-
  • R 12 is selected from hydrogen and C- ⁇ ealkyl, or R 1 1 and R 12 , together with the nitrogen atom to which they are bound, form a five or six-membered heterocyclic ring optionally containing one additional heteroatom selected from oxygen, sulfur and N-R 1 5;
  • R 13 is selected from C-j-galkyl, C- ⁇ alkoxy, -(CH2)p-C3_7cycloalkyl optionally substituted by one or more C-i- ⁇ alkyl groups, -CONR 9 R 10 , -NHCOR 1 °, halogen, CN, -(CH2) q NR 1 1 R 1 2 , trifluoromethyl, phenyl optionally substituted independently by one or more R 14 groups, heterocyclic optionally substituted independently by one or more R 14 groups, and a heteroaryl optionally substituted independently by one or more R 14 groups;
  • R 14 is selected from C-
  • R 15 is selected from hydrogen and methyl
  • X and Y are each independently selected from hydrogen, methyl and halogen
  • Z is selected from -(CH 2 ) S COOR 16 , or -(CH 2 ) S CONR 1 6R 1 7 ;
  • R 16 and R 17 are independently selected from hydrogen, optionally substituted C-
  • R 1 6 and R 17 together with the nitrogen atom to which they are bound, form an optionally substituted five- to six-membered ring optionally containing at least one additional heteroatom selected from oxygen, sulfur and N-R 1 5;
  • R 1 8 and R 19 are each independently selected from hydrogen and
  • C-i -galkyl optionally substituted by up to two hydroxy groups; or R 1 S and R 19 , together with the nitrogen atom to which they are bound, form a five- to six-membered ring, optionally containing one additional heteroatom selected from oxygen, sulfur and N-R 15 , and wherein the ring is optionally substituted by up to two groups independently selected from oxo, halogen and C-
  • R20 and R21 are independently selected from hydrogen or Ci -4 alkyl; m is 0 or an integer selected from 1 , 2, 3 and 4; p is 0 or an integer selected from 1 and 2; q is 0 or an integer selected from 1 , 2 and 3; r is 0 or an integer of 1 ; s is 0 or an integer selected from 1 , 2, 3 and 4; and t is 0 or an integer selected from 1 , 2, 3, 4, 5 and 6; v is an integer selected from 1 , 2, 3, 4, 5, and 6; or a pharmaceutically acceptable salt or derivative thereof.
  • R 1 is selected from hydrogen; a C-j- ⁇ alkyl optionally substituted by up to three groups independently selected from C-i- ⁇ alkoxy, halogen, hydroxy, and NR 1 1 R 12 ; a C3_7cycloalkyl optionally substituted by one or more C-i- ⁇ alkyl groups; an aryl; a heteroaryl; or a heterocyclic ring, and wherein the aryl, heteroaryl, and heterocyclic rings are all optionally substituted, independently, by up to three groups selected from R 5 and R 6 .
  • a representative example of R 1 as a C3_6cycloalkyl is an optionally substituted cyclopropyl, or cyclohexylring.
  • a representative example of R 1 as a Ci - ⁇ alkyl includes but is not limited to 2-methylpropyl, 1 , 2-dimethylpropyl, 2, 2- dimethylpropyl, or a 1 , 2, 2-trimethylpropyl group.
  • R 1 as an optionally substituted heteroaryl group include but are not limited to a thiazole ring, diazole, imidazole, or thiadiazole ring.
  • R 1 as an optionally substituted heterocyclic ring include but are not limited to a piperazine ring, a piperidine, or a pyrrolidinyl ring., In one embodiment R 1 is a phenyl ring optionally substituted R 5 or R 6 .
  • R 1 is selected from C-
  • R 1 is selected from an optionally substituted heteroaryl ring.
  • R 1 is an optionally substituted thiazole ring, pyrazole, diazole, imidazole, or thiadiazole ring.
  • R 2 is selected from hydrogen, C-i - ⁇ alkyl and
  • (CH2)n-C3--7cycloalkyl optionally substituted by one or more C- ⁇ alkyl groups or (CH2)rr ⁇ R 1 an d R 2 together with the nitrogen atom to which they are bound, form an optionally substituted four- to six-membered heterocyclic ring, which may also optionally contain at least one additional heteroatom selected from oxygen, nitrogen and sulfur.
  • This heterocyclic ring may be optionally substituted by up to three substituents, independently selected from C-
  • the (CH2)mR ⁇ an d R 2 cyclized ring may be an optionally substituted piperidine, piperazine, or pyrollidine ring, such as a 4- methyl-1-piperazinyl ring.
  • R 2 is hydrogen, or a branched or linear C-j ⁇ alkyl moiety, such as ethyl , such as methyl, ethyl, n-propyl, isopropyl, n-butyl. Or t- butyl.
  • R 2 is selected from hydrogen, C-
  • R is hydrogen, C1 -6 alkyl, halo-substituted-Ci-4 alkyl, or C3-7 cycloalkyl.
  • R 5 is selected from Chalky!, Ci - ⁇ alkoxy,
  • -(CH2)p-C3_7cycloalkyl optionally substituted by one or more C- ⁇ galkyl groups, -CONR9R1 O 1 -NHCOR 1 0, -SO 2 NHRS, -(CH 2 ) q NHSO 2 R 1 °, halogen, CN, OH, -(CH 2 )qNR 1 1 R1 2 , and trifluoromethyl.
  • R 5 is selected from C ⁇ alkyl, Ci-4alkoxy, -(CH2) q NHS ⁇ 2R 10 , halogen, -(CH2)qNR 1 1 R 12 and trifluoromethyl.
  • R 5 is a Ci_4alkyl, such as methyl, or is a Ci-4alkoxy, such as methoxy.
  • R 6 is selected from Ci ⁇ alkyl, C- ⁇ alkoxy, halogen, trifluoromethyl and -(CH2)qNR 1 1 R 12 .
  • R ⁇ is selected from C-
  • R 6 is a C-
  • R 8 is selected from hydrogen, Ci -galkyl, C3_7cycloalkyl optionally substituted by one or more C-
  • R 8 when R 8 is a heteroaryl ring optionally substituted by R 13 and/or R 14 the ring includes, but is not limited to, a furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl ring, or as further defined herein.
  • R 8 is a heteroaryl optionally substituted R 13 and/or R 14
  • the heteroaryl ring is suitably a pyrazole, 1 ,2,4-thiadiazole, 1 ,3- thiazole, isoxazole, isothiazole, oxadiazolyl, or a pyridine.
  • R 8 is selected from hydrogen, C3-7cycloalkyl optionally substituted by one or more C-j-galkyl groups, CONHR 9 , phenyl optionally substituted by R 13 and/or R 14 , and heteroaryl optionally substituted by R 13 and/or R 14 .
  • R 8 is selected from C3_7cycloalkyl, CONHR 9 , phenyl optionally substituted by R 13 and/or R 14 and heteroaryl optionally substituted by R 13 and/or R 14 .
  • p O.
  • a representative example of R 8 is Cs.gcycloalkyl, such as cyclopropyl.
  • R 8 is Ci_galkyl, OH, or a C-i- ⁇ alkyl optionally substituted by one or more hydroxyl groups.
  • R 9 and R 1 O are each independently selected from hydrogen and C-
  • R 1 1 is selected from hydrogen, C-
  • R 12 is selected from hydrogen and Cf . ⁇ alkyl, or R 1 1 and R 12 , together with the nitrogen atom to which they are bound, form a five or six- membered heterocyclic ring optionally further containing one additional heteroatom N-R 15 .
  • R 13 is selected from hydrogen, C*
  • R 14 is selected from hydrogen, Ci_6alkyl, C-i - ⁇ alkoxy, halogen, halo-substituted C1-4 alkyl, such as trifluoromethyl, and NR 1 1 R 12 .
  • R 13 is selected from C-
  • R 14 is selected from Ci_4alkyl, C-
  • R 13 and R 14 are independently selected from hydrogen or C-j _4alkyl.
  • R 15 is hydrogen, or methyl.
  • X and Y are each independently selected from hydrogen, methyl and halogen.
  • X and Y are each independently selected from hydrogen, chlorine and fluorine.
  • a representative example of halogen is fluorine.
  • a further representative example of X is hydrogen.
  • a representative example of Y is hydrogen.
  • Z is selected from -(CH2) S COOR 16 , or -(CH2) S CONR 1 6R 1 7 .
  • n one embodiment Z is -(CH2) S CONR 1 6 R 17 .
  • R 1 6 and R 17 are independently selected from hydrogen, optionally substituted Ci - ⁇ alkyl, -(CR2fj R 21 )V OR18 .
  • optionally substituted -(CR2 ⁇ R2i)t neteroc y saw ' optionally substituted -(CR20 R 2i)t C3_7cycloalkyl, optionally substituted -(CR20 R 21 )tC4-7cycloalkenyl, or R 16 and R 17 together with the nitrogen atom to which they are bound, form an optionally substituted five- to six-membered heterocyclic ring optionally containing at least one additional heteroatom selected from oxygen, sulfur and N-R 1 5.
  • v is an integer selected from 1 , 2, 3, 4, 5, and 6.
  • R 1 6 is hydrogen, C-i- ⁇ alkyl, Ci-6alkyl optionally substituted one or more times independently by hydroxyl, halogen, Ci-6alkoxy, and NR7R7 1 , wherein R7 and Ry are each independently hydrogen or C-1 -4 alkyl.
  • R 16 is propyl, isopropyl, 2-hydroxypropyl, 3- hydroxypropyl, 2,2,2-trifluoroethyl, dimethylamino)ethyl, hydrogen, 3- (ethyloxy)propyl, 5-hydroxypentyl, (dibutylamino)propyl, or 1 -(methylethyl)oxy)propyl.
  • the R 1 6 moiety when it is a C-i- ⁇ alkyl (branched or linear) is optionally substituted independently, one or more times by halogen, such as fluorine, chlorine, bromine or iodine; hydroxy; C1-6 alkoxy, such as methoxy or ethoxy; halosubstituted C-
  • .galkyl is optionally substituted by one or two hydroxy groups.
  • R16 JS an optionally substituted -( CR2 ⁇ R2i)t net ⁇ roar yl r i n 9 > optionally substituted -( CR2rjR2i)t ar y
  • the rings may be substituted independently, one or more times, suitably 1 to 3 times, by halogen, such as fluorine, chlorine, bromine or iodine; hydroxy; hydroxy substituted Ci-6alkyl; C1-6 alkoxy, such as methoxy or ethoxy; halosubstituted C1 -6 alkoxy; S(O)m' C1 -6 alkyl, such as methyl thio, methylsul
  • halosubstituted C1 -6 alky! such CF2CF2H, or CF3
  • an optionally substituted aryl such as phenyl, or an optionally substituted arylalkyl, such as benzyl or phenethyl, wherein these aryl containing moieties may also be substituted one to two times by halogen; hydroxy; hydroxy substituted alkyl; C1 -6 alkoxy; S(O)m'alkyl; amino, mono & di-substituted C1-4 alkyl amino; C1-4 alkyl, or CF3.
  • the rings are substituted by one or two groups independently selected from halogen, Ci _ealkyl and oxo, and C-
  • the ring includes, but is not limited to, a furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl ring, indolyl, isoindolyl, azaindolyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzofuranyl, benzothiophenyl, quinolyl, isoquinolyl, quinazolinyl, cinnolinyl or phthala
  • R 16 when R 16 is an optionally substituted -(CR2 ⁇ R2i)t neteroc y devis ring, the ring includes, but is not limited to, aziridinyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, piperidyl, piperazinyl, morpholino and thiomorpholino rings, or as further defined herein.
  • R 16 and R 17 together with the nitrogen atom to which they are bound form an optionally substituted five- to six-membered heterocyclic ring which ring may optionally containing at least one additional heteroatom selected from oxygen, sulfur and N-R 15 the cyclized ring may be optionally substituted, independently, one or more times by halogen, such as fluorine, chlorine, bromine or iodine; hydroxy; C1 -6 alkoxy, such as methoxy or ethoxy; halosubstituted Ci-6alkoxy; S(0)m' alkyl, such as methyl thio, methylsulfinyl or methyl sulfonyl, wherein m' is 0, 1 or 2; -C(O); NR7R7 1 , wherein R7 and Ry are each independently hydrogen or C1-4 alkyl, such as amino or mono or -disubstituted C1 -4 alkyl or wherein the R7 and R7 1 can together with the nitrogen to which they are
  • cyclized ring is a piperidine ring or a piperazinyl ring.
  • the cyclized ring is optionally substituted by Ci -6 alkyl, hydroxy or
  • R 1 6 and R 17 together form an optionally substituted piperidinyl or piperazinyl ring.
  • tne heteroaryl ring is an optionally substituted pyridine, thiazole, pyrrole, diazole, imidazole, or a thiadiazole ring.
  • R 1 6 is a thiazole ring.
  • tne heterocyclic ring is a piperazine ring, a piperidine, or a pyrrolidinyl ring.
  • R 16 is an optionally substituted -(CR20R21 )t ar y' ring
  • the aryl ring is an optionally substituted phenyl.
  • the phenyl is optionally substituted independently, 1 to 3 times by C1-6 alkyl, or
  • R 16 is an optionally substituted -(CR2fjR2i)t C3- 7 cycloalkyl.
  • R16 is selected from hydrogen, optionally substituted C 1 _ 6 alkyl; -(CR 2 ()R21 )vOR 1 8 , -(CR 2 nR21 )vNR 18 R 19 , -(CR 2 nR21 )v COOR1 8 , -(CR2 ⁇ R2i)t neteroar y'' -(CR2 ⁇ R2i)t neteroc y c '' C ' ar
  • R16 JS an optionally substituted (CR2 ⁇ R2i)t net ⁇ roar y
  • R 16 is an optionally substituted thiazolyl, optionally substituted phenyl, optionally substituted pyridine, optionally substituted imidazole, optionally substituted piperidinyl, optionally substituted piperazinyl, optionally substituted phenylC-i -galkyl, or optionally substituted pyrrolidinyl Ci_ ⁇ alkyl.
  • R16 is 1 ,3-thiazolyl, optionally substituted phenyl, pyridine, imidazole, piperidinyl, piperazinyl, benzyl, phenylbutyl, phenylethyl, pyrrolidinylethyl, pyrrolidinylmethyl, or (4-methylphenyl)methyl, or (1-ethyl-2- pyrrolidinyl)methyl.
  • R16 is 1 ,3-thiazolyl, and t is 0.
  • One representative example of R 16 is -(CR20 R 2i)v NR 18 R 1 9 .
  • R 1 6 include hydrogen; Ci- ⁇ alkyl optionally substituted by up to two hydroxy groups, in particular methyl, ethyl, n-propyl, 2- hydroxypropyl, 2,3-dihydroxypropyl, 4-hydroxybutyl and 2,2-dimethylpropyl; (CR20R21 )v O R1 8 : (CR20R2I )v NR 18 R 19 ; (CR20R2I )v NHSO 2 R 1 8 ;
  • heteroaryl ring optionally substituted by up to two groups independently selected from halogen, C-i- ⁇ alkyl and oxo.
  • the heteroaryl ring is a 5- membered ring containing up to three heteroatoms selected from oxygen, nitrogen and sulphur.
  • R 18 and R 1 9 are each independently selected from hydrogen and a C- ⁇ alkyl group which is optionally substituted by up to two hydroxy groups, or R 18 and R 19 , together with the nitrogen atom to which they are bound, form a five- to six-membered heterocyclic ring optionally containing one additional heteroatom selected from oxygen, sulfur and N-R 15 , wherein the ring is optionally substituted by up to two groups independently selected from oxo, halogen and C-
  • R 18 and R 19 are each independently selected from hydrogen and C-
  • R 18 and R 19 together with the nitrogen atom to which they are bound, form a five- to six-membered heterocyclic ring optionally containing oxygen, for example pyrrolidinyl or morpholinyl.
  • R20 and R21 are independently selected from hydrogen or Ci -4 alkyl.
  • m is 0 or an integer selected from 1 , 2, 3 and 4, wherein each carbon atom of the resulting carbon chain may be optionally substituted with up to two groups independently selected from C-i - ⁇ alkyl and halogen.
  • m is selected from 0, 1 and 2.
  • m is selected from 0 and 1.
  • a representative example of m is 1.
  • a further representative example of m is 0.
  • p is 0 or an integer selected from 1 and 2.
  • p is selected from 0 and 1.
  • a representative example of p is 0.
  • q is 0 or an integer selected from 1 , 2 and 3. In one embodiment, q is selected from 0 and 1.
  • r is 0 or an integer of 1. In one embodiment, r is 0.
  • s is 0 or an integer selected from 1 , 2, 3 and 4. In one embodiment, s is selected from 0 and 1. A representative example of s is 0. A further representative example of s is 1.
  • t is 0 or an integer selected from 1 , 2, 3, 4, 5 and 6. In one embodiment t is selected from 0, 1 , 2, 3 and 4. In another embodiment, t is 2, 3, and 4. In another embodiment, t is selected from 2 and 3. A representative example of t is 0, or 2. Further representative examples of t include 1 , 3 and 4.
  • Z is (CH2) S CONR 1 6R 1 7 , R 1 6 is 1 ,3-thiazolyl, t is 0,
  • R 2 is hydrogen
  • R 1 is Ci ⁇ alkyl, or C3-7cycloalkyl.
  • Another aspect of the invention are compounds represented by the formula :
  • R1 is selected from hydrogen; C-j-galkyl optionally substituted by up to three groups independently selected from C-i- ⁇ alkoxy, halogen and hydroxy; C-3-7cycloalkyl optionally substituted independently by one or more Ci ⁇ alkyl groups; an aryl, heteroaryl, or heterocyclic ring each optionally substituted, independently, by up to three groups selected from R ⁇ and R ⁇ ;
  • R 2 is hydrogen, C-i- ⁇ alkyl or a -(CH2)p-C3_7cycloalkyl optionally substituted independently by one or more C-
  • R 3 is halogen or methyl;
  • R 4 is hydrogen, C1-6 alkyl, halo-substituted-Ci-4 alkyl, or C3-7cycloalkyl;
  • R 5 is independently C-i-galkyl, OR 4 , -(CH 2 )p-C3-7cycloalkyl optionally substituted independently by one or more C-i- ⁇ alkyl groups, -CONR 9 Ri 0 , -NHCOR 1 0, -SO 2 NHRS, -(CH 2 )qNHSO 2 R 1 °, halogen, CN 1 -(CH 2 ) q NR 1 1 R 12 , and trifluoromethyl;
  • R ⁇ is independently hydrogen, C-i-galkyl, OR 4 , halogen, trifluoromethyl and -(CH 2 ) q NR 1 1 R 12 ;
  • R 8 is selected from hydrogen, C- ⁇ galkyl, C3_7cycloalkyl optionally substituted by one or more Ci. ⁇ alkyl groups, OH, a C-
  • R 9 and R 10 are each independently selected from hydrogen and C-
  • R 9 and R 10 together with the nitrogen atom to which they are bound, form a five- to six-membered heterocyclic ring optionally containing one additional heteroatom selected from oxygen, sulfur and N-R 15 , wherein the ring is optionally substituted by up to two C-j-galkyl groups;
  • R 1 1 is selected from hydrogen, Ci ⁇ alkyl and -(CH 2 )p-C3_7cycloalkyl optionally substituted by one or more C-j.galkyl groups,
  • R 1 2 is selected from hydrogen and C-
  • R 1 1 and R 12 together with the nitrogen atom to which they are bound, form a five or six-membered heterocyclic ring optionally containing one additional heteroatom selected from oxygen, sulfur and N-R 1 5;
  • R 13 is selected from C- ⁇ ealkyl, C-i -galkoxy, -(CH 2 )p-C3_7cycloalkyl optionally substituted by one or more C ⁇ .galkyl groups, -CONR 9 R 1 0 , -NHCOR 10 , halogen, CN, -(CH 2 ) q NR 1 1 R 12 , trifluoromethyl, phenyl optionally substituted independently by one or more R 14 groups, heterocyclic optionally substituted independently by one or more R 14 groups, and a heteroaryl optionally substituted independently by one or more R 14 groups;
  • R 14 is selected from C- ⁇ alkyl, C-i.galkoxy, halogen, halo-substituted C1 -4 alkyl, and NR 1 1 R 12 ;
  • R 1 5 js selected from hydrogen and methyl
  • X and Y are each independently selected from hydrogen, methyl and halogen
  • Z is selected from -(CH 2 ) S NH 2 , or (CH 2 ) S N(R 22 )CONR 23 R 24 ;
  • R 23 and R 24 are independently selected from hydrogen, optionally substituted Ci- 6 alkyl, -(CR 2 oR2i)vOR 25 , -(CR 2 OR21 )V N R25 R 26 - -(CR 20 R 2 I )vNHSO 2 R 25 , -(CR 2 OR21 )VCONR 2 5R 2 6 J -(CR 2 OR21 )V COOR 25 , optionally substituted -(CR 2 oR 2 i)theteroaryl, optionally substituted -(CR 20 R 2 I )t aryl, optionally substituted -(CR 20 R 2 I ⁇ heterocyclic, optionally substituted -(CR 2 QR2i )t C3_7cycloalkyl, or optionally substituted -(CR 2 QR 2 I )t C3_7cycloal
  • R 23 and R 25 together with the nitrogen atom to which they are bound, form an optionally substituted five- to six-membered ring optionally containing at least one additional heteroatom selected from oxygen, sulfur and N-R 15 ;
  • R 25 and R 26 are each independently selected from hydrogen and C-
  • R 25 and R 26 together with the nitrogen atom to which they are bound, form a five- to six-membered ring, optionally containing one additional heteroatom selected from oxygen, sulfur and N-R 1 5, and wherein the ring is optionally substituted by up to two groups independently selected from oxo, halogen and C-
  • R 2 O and R 2 i are independently selected from hydrogen or Ci -4 alkyl
  • R 22 is selected from hydrogen or Ci -4 alkyl; " m is 0 or an integer selected from 1 , 2, 3 and 4; p is 0 or an integer selected from 1 and 2; q is 0 or an integer selected from 1 , 2 and 3; r is 0 or an integer of 1 ; s is 0 or an integer selected from 1 , 2, 3 and 4; and t is 0 or an integer selected from 1 , 2, 3, 4, 5 and 6; v is an integer selected from 1 , 2, 3, 4, 5 and 6; or a pharmaceutically acceptable salt or derivative thereof.
  • Z is -(CH 2 ) S NH 2> or (CH 2 ) S N(R 22 )CONR 23 R 24 . in one embodiment Z is (CH 2 ) S N(R 22 )CONR 23 R 24 .
  • R 23 and R 24 are independently selected from hydrogen, optionally substituted Ci .galkyl, -(CR 2 QR 2 I ) V OR 25 , -(CR 2 OR 2 I ) V NR 25 R 26 , -(CR 20 R 2 I ) V NHSO 2 R 25 , -(CR 2 oR 2 i ) V CONR 25 R 26 , -(CR 20 R 2 I ) v COOR 25 , optionally substituted -(CR 2 oR 2 i)theteroaryl, optionally substituted -(CR 2 oR 2 i)t aryl, optionally substituted -(CR 2 oR 2 i)theterocyclic, optionally substituted -(CR2 ⁇ R2i )t C3.7cycloalkyl, or optionally substituted -(CR2oR2i)t C3.7cycloalkenyl; or R 2 ⁇ and R 24 , together with the nitrogen atom to which they are bound, form an optionally
  • R 25 and R 26 are each independently selected from hydrogen and Ci - ⁇ alkyl optionally substituted by up to two hydroxy groups; or R 25 and
  • R 26 together with the nitrogen atom to which they are bound, form a five- to six- membered ring, optionally containing one additional heteroatom selected from oxygen, sulfur and N-R 15 , and wherein the ring is optionally substituted by up to two groups independently selected from oxo, halogen and C- ⁇ alkyl.
  • R20 and R21 are independently selected from hydrogen or Ci -4 alkyl.
  • v is an integer selected from 1 , 2, 3, 4, 5 and 6.
  • R 22 is selected from hydrogen or Ci -4 alkyl.
  • This invention therefore also relates to the novel compounds of Formula (A), and pharmaceutical compositions comprising a compound of Formula (A), and a pharmaceutically acceptable diluent or carrier.
  • This invention relates to a method of treating a CSBP/RK/p38 kinase mediated disease, and the inflammation associated therewith, in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound of Formula (A).
  • This invention also relates to a method of inhibiting cytokines and the treatment of a cytokine mediated disease, and the inflammation associated therewith, in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound of Formula (A).
  • This invention more specifically relates to a method of inhibiting the production of IL-1 , IL-8, or TNF in a mammal in need thereof which comprises administering to said mammal an effective amount of a compound of Formula (A).
  • the present invention covers all combinations of the representative groups described hereinabove. It is also to be understood that the present invention encompasses compounds of formula (I) in which a particular group or parameter, for example R 5 , R ⁇ , R9, R10, R1 1 , R1 2 , R-IS 1 p or q may occur more than once. In such compounds it will be appreciated that each group or parameter is independently selected from the values listed. Particular compounds according to the invention include those mentioned in the examples and their pharmaceutically derivatives.
  • salts and solvates of compounds of the invention which are suitable for use in medicine are those wherein the counterion or associated solvent is pharmaceutically acceptable.
  • salts and solvates having non-pharmaceutically acceptable counterions or associated solvents are within the scope of the present invention, for example, for use as intermediates in the preparation of other compounds of the invention and their pharmaceutically acceptable salts and solvates.
  • the term "pharmaceutically acceptable derivative” means any pharmaceutically acceptable salt, solvate or prodrug e.g. ester, of a compound of the invention, which upon administration to the recipient is capable of providing (directly or indirectly) a compound of the invention, or an active metabolite or residue thereof.
  • Such derivatives are recognizable to those skilled in the art, without undue experimentation. Nevertheless, reference is made to the teaching of Burger's Medicinal Chemistry and Drug Discovery, 5 th Edition, Vol. 1 : Principles and Practice, which is incorporated herein by reference to the extent of teaching such derivatives.
  • the pharmaceutically acceptable derivatives are salts, solvates, esters, carbamates and phosphate esters.
  • the pharmaceutically acceptable derivatives are salts, solvates and esters.
  • the pharmaceutically acceptable derivatives are salts and esters, in particular salts.
  • the compounds of the present invention may be in the form of and/or may be administered as a pharmaceutically acceptable salt.
  • suitable salts see Berge et al., J. Pharm. Sci., 1977, 66, 1 -19.
  • a pharmaceutical acceptable salt may be readily prepared by using a desired acid or base as appropriate.
  • the salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.
  • Salts of the compounds of the present invention may, for example, comprise acid addition salts resulting from reaction of an acid with a nitrogen atom present in a compound of formula (I). Salts encompassed within the term "pharmaceutically acceptable salts" refer to non-toxic salts of the compounds of this invention.
  • Suitable addition salts are formed from acids which form non-toxic salts and examples are acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, ethanesulphonate, formate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydrogen phosphate, hydroiodide, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulf
  • Pharmaceutically acceptable base salts include ammonium salts such as a trimethylammonium salt, alkali metal salts such as those of sodium and potassium, alkaline earth metal salts such as those of calcium and magnesium and salts with organic bases, including salts of primary, secondary and tertiary amines, such as isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexyl amine and N-methyl-D-glucamine.
  • ammonium salts such as a trimethylammonium salt
  • alkali metal salts such as those of sodium and potassium
  • alkaline earth metal salts such as those of calcium and magnesium
  • salts with organic bases including salts of primary, secondary and tertiary amines, such as isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexyl amine and N-methyl-D-glucamine.
  • solvates refers to a complex of variable stoichiometry formed by a solute (in this invention, a compound of formula (I) or a salt thereof) and a solvent.
  • solvents for the purpose of the invention may not interfere with the biological activity of the solute.
  • suitable solvents include water, methanol, ethanol and acetic acid.
  • the solvent used is a pharmaceutically acceptable solvent.
  • suitable pharmaceutically acceptable solvents include water, ethanol and acetic acid.
  • the solvent used is water.
  • a complex with water is known as a "hydrate”. Solvates of the compound of the invention are within the scope of the invention.
  • prodrug means a compound which is converted within the body, e.g. by hydrolysis in the blood, into its active form that has medical effects.
  • Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series; Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987; and in D. Fleisher, S. Ramon and H. Barbra "Improved oral drug delivery: solubility limitations overcome by the use of prodrugs", Advanced Drug Delivery Reviews (1996) 19(2) 115-130, each of which are incorporated herein by reference.
  • Prodrugs are any covalently bonded carriers that release a compound of formula (I) in vivo when such prodrug is administered to a patient.
  • Prodrugs are generally prepared by modifying functional groups in a way such that the modification is cleaved, either by routine manipulation or in vivo, yielding the parent compound.
  • Prodrugs include, for example, compounds of this invention wherein hydroxy or amine groups are bonded to any group that, when administered to a patient, cleaves to form the hydroxy or amine groups.
  • representative examples of prodrugs include (but are not limited to) acetate, formate and benzoate derivatives of alcohol and amine functional groups of the compounds of formula (I).
  • esters may be employed, such as methyl esters, ethyl esters, and the like. Esters may be active in their own right and /or be hydrolysable under in vivo conditions in the human body. Suitable pharmaceutically acceptable in vivo hydrolysable ester groups include those which break down readily in the human body to leave the parent acid or its salt.
  • alkyl refers to straight or branched hydrocarbon chains containing the specified number of carbon atoms.
  • C-i ⁇ alkyl means a straight or branched alkyl containing at least 1 , and at most 6, carbon atoms.
  • alkyl as used herein include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, isobutyl, isopropyl, sec-butyl, t-butyl and hexyl and the like.
  • alkenyl refers to straight or branched hydrocarbon chains containing the specified number of carbon atoms and containing at least one double bond.
  • C-2-6alkenyl means a straight or branched alkenyl containing at least 2, and at most 6, carbon atoms and containing at least one double bond.
  • alkenyl as used herein include, but are not limited to ethenyl, 2-propenyl, 3-butenyl, 2-butenyl, 2- pentenyl, 3-pentenyl, 3-methyl-2-butenyl, 3-methylbut-2-enyl, 3-hexenyl, 1 ,1- dimethylbut-2-enyl and the like.
  • aryl refers to phenyl and naphthyl.
  • alkoxy refers to straight or branched chain alkoxy groups containing the specified number of carbon atoms.
  • C- ] . ⁇ alkoxy means a straight or branched alkoxy containing at least 1 , and at most 6, carbon atoms.
  • alkoxy as used herein include, but are not limited to, methoxy, ethoxy, propoxy, prop-2-oxy, butoxy, but-2-oxy, 2- methylprop-1-oxy, 2-methylprop-2-oxy, pentoxy and hexyloxy.
  • cycloalkyl refers to a non-aromatic hydrocarbon ring containing the specified number of carbon atoms. For example, C3.
  • 7cycloalkyl means a non-aromatic ring containing at least three, and at most seven, ring carbon atoms.
  • Representative examples of "cycloalkyl” as used herein include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • heteroaryl ring and “heteroaryl” refer to a monocyclic five- to seven- membered unsaturated hydrocarbon ring containing at least one heteroatom selected from oxygen, nitrogen and sulfur.
  • heteroaryl rings include, but are not limited to, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl.
  • heteroaryl ring and “heteroaryl” also refer to fused aromatic rings comprising at least one heteroatom selected from oxygen, nitrogen and sulfur. Preferably, the fused rings each have five or six ring atoms.
  • fused aromatic rings include, but are not limited to, indolyl, isoindolyl, azaindolyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzofuranyl, benzothiophenyl, quinolyl, isoquinolyl, quinazolinyl, cinnolinyl and phthalazinyl.
  • heterocyclic rings and “heterocyclyl” refer to a monocyclic three- to seven-membered saturated or non-aromatic, unsaturated hydrocarbon ring containing at least one heteroatom selected from oxygen, nitrogen and sulfur.
  • heterocyclyl groups include, but are not limited to, aziridinyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, piperidyl, piperazinyl, morpholino and thiomorpholino.
  • aralkyl or “heteroarylalkyl” or “heterocyclicalkyl” is used herein to mean a C1 -4 alkyl linkage, unless the carbon chain linkage is otherwise indicated which may be straight or branched, as defined above, and which carbon chain is attached to the aryl, cycloalkyl, heteroaryl or heterocyclic moiety.
  • halogen or halo refer to the elements fluorine, chlorine, bromine and iodine.
  • the term "optionally” means that the subsequently described event(s) may or may not occur, and includes both event(s) which occur and events that do not occur.
  • substituted refers to substitution with the named substituent or substituents, multiple degrees of substitution being allowed unless otherwise stated.
  • substituted or “optionally substituted” unless specifically defined elsewhere shall mean such groups as halogen, such as fluorine, chlorine, bromine or iodine; hydroxy; hydroxy substituted Ci- ⁇ alkyl; C-1-6 alkoxy, such as methoxy or ethoxy; halosubstituted C1-6 alkoxy; S(0)m' alkyl, such as methyl thio, methylsulfinyl or methyl sulfonyl, wherein m' is 0, 1 or 2; -C(O); NR7R7 1 , wherein R7 and R7' are each independently hydrogen or C-1.4 alkyl, such as amino or mono or -disubstituted C-1.4 alkyl or wherein the R7R7 1 can cyclize together with the nitrogen to which they are attached to form a 5 to 7 membered ring which optionally contains an additional heteroatom selected from O/N/S; C1-6 alkyl, C3
  • halosubstituted C1-6 alkyl such CF2CF2H, or CF3
  • an optionally substituted aryl such as phenyl, or an optionally substituted arylalkyl, such as benzyl or phenethyl, wherein these aryl containing moieties may also be substituted one to two times by halogen; hydroxy; hydroxy substituted alkyl; C1-6 alkoxy; S(O)m'alkyl; amino, mono & di-substituted C1 -4 alkyl amino; C1-4 alkyl, or CF3.
  • the compounds of structure (I) may have one or more asymmetric carbon atom and may occur as racemates, racemic mixtures and as individual enantiomers or diastereomers. All such isomeric forms are included within the present invention, including mixtures thereof.
  • Cis (E) and trans (Z) isomerism may also occur.
  • the present invention includes the individual stereoisomers of the compound of the invention and, where appropriate, the individual tautomeric forms thereof, together with mixtures thereof.
  • Separation of diastereoisomers or cis and trans isomers may be achieved by conventional techniques, e.g. by fractional crystallisation, chromatography or H. P. L. C.
  • a stereoisomeric mixture of the agent may also be prepared from a corresponding optically pure intermediate or by resolution, such as H.P.L.C. of the corresponding racemate using a suitable chiral support or by fractional crystallisation of the diastereoisomeric salts formed by reaction of the corresponding racemate with a suitable optically active acid or base, as appropriate.
  • crystalline forms of the compounds of structure (I) may exist as polymorphs, which are included in the present invention.
  • the compounds of this invention may be made by a variety of methods, including standard chemistry. Any previously defined variable will continue to have the previously defined meaning unless otherwise indicated. Illustrative general synthetic methods are set out below and then specific compounds of the . invention are prepared in the working Examples.
  • a compound of formula (I) may be prepared by reacting a compound of (II)
  • R 3 , p, X and Y are as hereinbefore defined, for formula (I), and wherein R 8 is selected from hydrogen, C- ⁇ alkyl, C3_7cycloalkyl optionally substituted by one or more C-i ⁇ alkyl groups, CONHR 9 , phenyl optionally substituted by R 13 and/or R14 ( and heteroaryl optionally substituted by R ⁇ 3 and/or R ⁇ 1 wherein R 9 , R 13 and R1 4 , are as defined in formula (I); in the presence of a catalyst, for example tetrakis(triphenylphosphine)palladium.
  • a compound of formula (II) may readily be prepared from a corresponding acid compound of formula (IV)
  • Suitable amide forming conditions are well known in the art and include treating a solution of the acid of formula (IV), or the activated form thereof, in for example acetone or dichloromethane, with an amine of formula (V) in the presence of sodium carbonate.
  • a compound of formula (III) may be prepared by reacting a compound of formula (Vl)
  • a compound of formula (III) may be prepared by reacting an acid compound of formula (VII)
  • a compound of formula (I) may also be prepared by reacting a compound of formula (VIII)
  • a compound of formula (I) may be prepared by reacting a compound of (II) as hereinbefore defined with a compound of formula (IX)
  • a compound of formula (I) may be prepared by reacting a compound of formula (X)
  • a compound of formula (X) may be prepared by reacting a compound of formula (Xl)
  • a further general method comprises final stage modification of one compound of formula (I) into another compound of formula (I).
  • Suitable functional group transformations for converting one compound of formula (I) into another compound of formula (I) are well known in the art and are described in, for instance, Comprehensive Heterocyclic Chemistry II, eds. A. R. Katritzky, C. W. Rees and E. F. V. Scriven (Pergamon Press, 1996), Comprehensive Organic Functional Group Transformations, eds. A.R. Katritzky, O. Meth-Cohn and CW. Rees (Elsevier Science Ltd., Oxford, 1995), Comprehensive Organic Chemistry, eds. D. Barton and W. D. Ollis (Pergamon Press, Oxford, 1979), and Comprehensive Organic Transformations, R. C. Larock (VCH Publishers Inc., New York, 1989).
  • a compound of formula (I) may be prepared from a compound of formula (XII)
  • Z' is a group convertible to Z as defined for formula (I). Conversion of a Z' group may arise if, for example, an alternative group such as a halogen group or a protecting group is present during the reactions described above.
  • an alternative group such as a halogen group or a protecting group is present during the reactions described above.
  • a comprehensive discussion of protecting groups and methods for cleaving protected derivatives is given in for example T.W. Greene and P. G. M Wuts in Protective Groups in Organic Synthesis 2 nd ed., John Wiley & Son, lnc 1991.
  • Scheme 2 i. Bis(pinnacolato)diboron, PdCI 2 dppf, KOAc, DMF. ii. R8(CH 2 )pNH 2) HATU, DIPEA, DMF. iii. SOCI 2 iv. R 1 (CH 2 ) m NHR 2 , Na 2 CO 3 , DCM. v. Na 2 CO 3 , tetrakis(triphenylphosphine)palladium, propan-2-ol.
  • another general method for preparing the compounds of formula (I) comprises the reactions set out in Scheme 3 below.
  • isocyanate to form urea
  • Suitable protecting groups for use according to the present invention are well known to those skilled in the art and may be used in a conventional manner. See, for example, "Protective groups in organic synthesis” by T.W. Greene and P.G.M. Wuts (John Wiley & sons 1991) or "Protecting Groups” by P.J. Kocienski (Georg Thieme Verlag 1994).
  • suitable amino protecting groups include acyl type protecting groups (e.g.
  • aromatic urethane type protecting groups e.g. benzyloxycarbonyl (Cbz) and substituted Cbz
  • aliphatic urethane protecting groups e.g. 9-fluorenylmethoxycarbonyl (Fmoc), t-butyloxycarbonyl (Boc), isopropyloxycarbonyl, cyclohexyloxycarbonyl
  • alkyl type protecting groups e.g. benzyl, trityl, chlorotrityl.
  • oxygen protecting groups may include for example alky silyl groups, such as trimethylsilyl or tert- butyldimethylsilyl; alkyl ethers such as tetrahydropyranyl or tert-butyl; or esters such as acetate.
  • alky silyl groups such as trimethylsilyl or tert- butyldimethylsilyl
  • alkyl ethers such as tetrahydropyranyl or tert-butyl
  • esters such as acetate.
  • the compounds of Formula (I), or a pharmaceutically acceptable salt or derivative thereof can be used in the manufacture of a medicament for the prophylactic or therapeutic treatment of any disease state in a human, or other mammal, in which and underlying inflammatory condition is demonstrated by, exacerbated by, and amplified by excessive cytokine, chemokine and adhesion molecule production by such mammal's cell, such as, but not limited to, monocytes, macrophages, neutrophils, endothelial cells or smooth muscle cells.
  • the compounds of the present invention are generally inhibitors of the serine/threonine kinase p38 and are therefore also inhibitors of cytokine production which is mediated by p38 kinase.
  • inhibitors of the serine/threonine kinase p38 are included those compounds that interfere with the ability of p38 to transfer a phosphate group from ATP to a protein substrate according to the assay described below.
  • the compounds of the invention may be selective for one or more of the isoforms of p38, for example p38 ⁇ , p38 ⁇ , p38 ⁇ and/or p38 ⁇ .
  • the compounds of the invention selectively inhibit the p38 ⁇ isoform.
  • the compounds of the invention selectively inhibit the p38 ⁇ isoform.
  • the compounds of the invention selectively inhibit the p38 ⁇ and p38 ⁇ isoforms.
  • Assays for determining the selectivity of compounds for the p38 isoforms are described in, for example, WO 99/61426, WO 00/71535 and WO 02/46158.
  • p38 kinase activity can be elevated (locally or throughout the body), p38 kinase can be incorrectly temporally active or expressed, p38 kinase can be expressed or active in an inappropriate location, p38 kinase can be constitutively expressed, or p38 kinase expression can be erratic; similarly, cytokine production mediated by p38 kinase activity can be occurring at inappropriate times, inappropriate locations, or it can occur at detrimentally high levels.
  • the present invention provides a method for the treatment of a condition or disease state mediated by p38 kinase activity, or mediated by cytokines produced by the activity of p38 kinase, in a subject which comprises administering to said subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable derivative thereof.
  • the compound may be administered as a single or polymorphic crystalline form or forms, an amorphous form, a single enantiomer, a racemic mixture, a single stereoisomer, a mixture of stereoisomerism, a single diastereoisomer or a mixture of diastereoisomers.
  • the present invention treats these conditions by providing a therapeutically effective amount of a compound of this invention.
  • therapeutically effective amount is meant a symptom-alleviating or symptom- reducing amount, a cytokine-reducing amount, a cytokine-inhibiting amount, a kinase-regulating amount and/or a kinase-inhibiting amount of a compound.
  • Such amounts can be readily determined by standard methods, such as by measuring cytokine levels or observing alleviation of clinical symptoms. For example, the clinician can monitor accepted measurement scores for anti- inflammatory treatments. It will be appreciated that reference to treatment includes acute treatment or prophylaxis as well as the alleviation of established symptoms.
  • Compounds of Formula (I) are capable of inhibiting proinflammatory mediators in the form of cytokines or chemokines, such as IL-1 , IL-6, IL-8, TNF and RANTES and are therefore of use in therapy for diseases with an inflammatory component.
  • IL-1 , IL-6, IL-8, RANTES and TNF as well as other cytokines and chemokines affect a wide variety of cells and tissues, are important and critical inflammatory mediators of a wide variety of disease states and conditions.
  • These pro-inflammatory mediators are produced by leukocytes as well as epithelial cells, endothelial cells, smooth muscle cells and other resident cells. The inhibition of these pro-inflammatory cytokines and chemokines is of benefit in controlling, reducing and alleviating many disease states which are marked by the excess production of these mediators.
  • the present invention provides a method of treating an inflammatory disease, which comprises administering an effective cytokine- interfering amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • compounds of Formula (I) or a pharmaceutically acceptable salt thereof are of use in the prophylaxis or therapy of any disease state in a human, or other mammal, which is exacerbated by or caused by excessive inflammatory mediator production, such as IL-1 , IL-6, IL-8 or TNF, by such mammal's cells, such as, but not limited to, monocytes, macrophages, neutrophils and endothelial cells.
  • IL-1 , IL-6, IL-8 or TNF excessive inflammatory mediator production
  • monocytes such as, macrophages, neutrophils and endothelial cells.
  • cytokine and chemokine production are the biomarkers of inflammatory diseases, and can be measured in serum or tissue samples from patients affected with these diseases.
  • Excessive cytokine production is implicated in exacerbating and amplifying or perpetuating inflammatory diseases which include rheumatoid arthritis, osteoarthritis, meningitis, ischemic and hemorrhagic stroke, neurotrauma/closed head injury, stroke, 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 and associated disorders (mycardial infarction and stroke), muscle degeneration, pulmonary inflammation in asthma or chronic obstructive pulmonary disease (COPD), multiple sclerosis, cachexia, bone resorption, psoriatic arthritis, Reiter's syndrome, gout, traumatic arthritis, rubella arthritis and acute synovitis, progressive renal disease (diabetic and non-diabetic), hypertension and salt- sensitive hypertension. Recent evidence also links inflammation as measured by excess IL-1 levels to diabetes, pancreatic
  • a p38 inhibitor compound for the treatment of p38 mediated disease states can include, but not be limited to neurodegenerative diseases, such as Alzheimer's disease (as noted above), Parkinson's disease and multiple sclerosis, etc.
  • this invention relates to a method of inhibiting the production of TNF in a mammal in need thereof which comprises administering to said mammal an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • Excessive or unregulated TNF production has been implicated in mediating or exacerbating a number of inflammatory diseases including rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions, sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, chronic obstructive pulmonary disease, silicosis, pulmonary sarcoisosis, bone resorption diseases, such as osteoporosis, cardiac, brain and renal reperfusion injury, graft vs.
  • inflammatory diseases including rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions, sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, chronic obstructive pulmonary disease,
  • allograft rejections fever and myalgias due to infection, such as influenza, brain infections including encephalitis (including HIV-induced forms), cerebral malaria, meningitis, ischemic and hemorrhagic stroke, cachexia secondary to infection or malignancy, cachexia secondary to acquired immune deficiency syndrome (AIDS), AIDS, ARC (AIDS related complex), keloid formation, scar tissue formation, inflammatory bowel disease, Crohn's disease, ulcerative colitis and pyresis.
  • encephalitis including HIV-induced forms
  • cerebral malaria meningitis
  • ischemic and hemorrhagic stroke cachexia secondary to infection or malignancy
  • cachexia secondary to acquired immune deficiency syndrome (AIDS) AIDS
  • AIDS AIDS
  • ARC AIDS related complex
  • keloid formation scar tissue formation
  • scar tissue formation inflammatory bowel disease
  • Crohn's disease Crohn's disease
  • ulcerative colitis pyresis.
  • Compounds of Formula (I) are capable of inhibiting inducible proinflammatory proteins, such as COX-2, also referred to by many other names such as prostaglandin endoperoxide synthase-2 (PGHS-2) and iNOS and are therefore of use in therapy.
  • Proinflammatory lipid mediators of the cyclooxygenase (CO) pathway are produced by the inducible COX-2 enzyme. Regulation, therefore of COX-2 which is responsible for the these products derived from arachidonic acid, such as prostaglandins affect a wide variety of cells and tissues are important and critical inflammatory mediators of a wide variety of disease states and conditions. Expression of COX-1 is not effected by compounds of Formula (I).
  • This selective inhibition of COX-2 may alleviate or spare ulcerogenic liability associated with inhibition of COX-1 thereby inhibiting prostaglandins essential for cytoprotective effects.
  • inhibition of these pro-inflammatory mediators is of benefit in controlling, reducing and alleviating many of these disease states.
  • Most notably these inflammatory mediators, in particular prostaglandins, have been implicated in pain, such as in the sensitization of pain receptors, or edema.
  • This aspect of pain management therefore includes treatment of neuromuscular pain, headache, cancer pain, arthritis pain and dental pain.
  • Compounds of Formula (I) or a pharmaceutically acceptable salt thereof are of use in the prophylaxis or therapy in a human, or other mammal, by inhibition of the synthesis of the COX-2 enzyme.
  • the present invention provides a method of inhibiting the synthesis of COX-2 which comprises administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • the present invention also provides for a method of prophylaxis treatment in a human, or other mammal, by inhibition of the synthesis of the COX-2 enzyme.
  • viruses of Formula (I) are also useful in the treatment of viral infections, where such viruses are sensitive to upregulation by TNF or will elicit TNF production in vivo.
  • the viruses contemplated for treatment herein are those that produce TNF as a result of infection, or those which are sensitive to inhibition, such as by decreased replication, directly or indirectly, by the TNF inhibiting-compounds of Formula (1).
  • viruses include, but are not limited to HIV-1 , HIV-2 and HIV-3, Cytomegalovirus (CMV), Influenza, adenovirus and the Herpes group of viruses, such as but not limited to, Herpes Zoster and Herpes Simplex.
  • this invention relates to a method of treating a mammal afflicted with a human immunodeficiency virus (HIV) which comprises administering to such mammal an effective TNF inhibiting amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • Compounds of Formula (I) are also useful in treatment of the host response to additional viral infections.
  • This additional aspect of the present invention is a method of treating the common cold or respiratory viral infection caused by human rhinovirus (HRV), other enteroviruses, coronavirus, influenza virus, parainfluenza virus, respiratory syncytial virus, or adenovirus in a human in need thereof which method comprises administering to said human an effective amount of a CBSP/p38 inhibitor.
  • HRV human rhinovirus
  • the treatment herein is not directed to the elimination or treatment of the viral organism itself but is directed to treatment of the respiratory viral infection that exacerbates other diseases or symptoms of disease, such as asthma (exacerbated by such infections), chronic bronchitis, chronic obstructive pulmonary disease, otitis media, and sinusitis.
  • Another aspect of the present invention is a method of treating, including prophylaxis of influenza induced pneumonia in a human in need thereof which method comprises administering to said human an effective amount of a CBSP/p38 inhibitor.
  • the present invention also relates to the use of the CSBP/p38 kinase inhibitor for the treatment, including prophylaxis, of inflammation associated with a viral infection of a human rhinovirus (HRV), other enteroviruses, coronavirus, influenza virus, parainfluenza virus, respiratory syncytial virus, or adenovirus.
  • HRV human rhinovirus
  • the present invention is directed to the treatment of a viral infection in a human, which is caused by the human rhinovirus (HRV), other enterovirus, coronavirus, influenza virus, parainfluenza virus, respiratory syncytial virus, or an adenovirus.
  • HRV human rhinovirus
  • the invention is directed to respiratory viral infections that exacerbate asthma (induced by such infections), chronic bronchitis, chronic obstructive pulmonary disease, otitis media, and sinusitis.
  • IL-8 or other cytokines While inhibiting IL-8 or other cytokines may be beneficial in treating a rhinovirus may be known, the use of an inhibitor of the p38 kinase for treating HRV or other respiratory viral infections causing the common cold is believed novel.
  • the respiratory viral infection treated herein may also be associated with a secondary bacterial infection, such as otitis media, sinusitis, or pneumonia.
  • treatment may include prophylaxis for use in a treatment group susceptible to such infections. It may also include reducing the symptoms of, ameliorating the symptoms of, reducing the severity of, reducing the incidence of, or any other change in the condition of the patient, which improves the therapeutic outcome.
  • a preferred viral infection for treatment herein is the human rhinovirus (HRV) or respiratory syncytial virus (RSV).
  • Epithelial cells represent the primary site of infection of HRV. Therefore another aspect of the present invention is a method of treatment to reduce inflammatory response associated with a rhinovirus infection, not necessarily a direct effect on virus itself.
  • Compounds of Formula (I) may also be used in association with the veterinary treatment of mammals, other than in humans, in need of inhibition of TNF production.
  • TNF mediated diseases for treatment, therapeutically or prophylactically, in animals include disease states such as those noted above, but in particular viral infections.
  • viruses include, but are not limited to, lentivirus infections such as, equine infectious anaemia virus, caprine arthritis virus, visna virus, or maedi virus or retrovirus infections, such as but not limited to feline immunodeficiency virus (FIV), bovine immunodeficiency virus, or canine immunodeficiency virus or other retroviral infections.
  • lentivirus infections such as, equine infectious anaemia virus, caprine arthritis virus, visna virus, or maedi virus or retrovirus infections, such as but not limited to feline immunodeficiency virus (FIV), bovine immunodeficiency virus, or canine immunodeficiency virus or other retroviral infections.
  • FMV feline immunodeficiency virus
  • bovine immunodeficiency virus bovine immunodeficiency virus
  • canine immunodeficiency virus or other retroviral infections such as but not limited to feline immunodeficiency virus (FIV), bovine immunodeficiency virus, or canine immunodefic
  • this invention relates to a method of inhibiting the production of IL-8 in a mammal in need thereof which comprises administering to said mammal an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • IL-8 IL-8
  • neutrophils such as, psoriasis, inflammatory bowel disease, asthma, cardiac, brain and renal reperfusion injury, adult respiratory distress syndrome, thrombosis and glomerulonephritis. All of these diseases are associated with increased IL-8 production which is responsible for the chemotaxis of neutrophils into the inflammatory site.
  • IL-8 In contrast to other inflammatory cytokines (IL-1 , TNF, and IL-6), IL-8 has the unique property of promoting neutrophil chemotaxis and activation. Therefore, the inhibition of IL-8 production would lead to a direct reduction in the neutrophil infiltration.
  • An additional aspect of the invention is treatment of chronic diseases which have an inappropriate angiogenic component including various ocular neovasularizations, such as diabetic retinopathy and macular degeneration.
  • chronic diseases which have an excessive or increased proliferation of vasculature are tumor growth and metastasis, atherosclerosis, and certain arthritic conditions. Therefore p38 kinase inhibitors will be of utility in the blocking of the angiogenic component of these disease states.
  • vasculature inappropriate angiogenesis includes, but is not limited to, diseases which are characterized by hemangiomas and ocular diseases.
  • inappropriate angiogenesis includes, but is not limited to, diseases which are characterized by vesicle proliferation with accompanying tissue proliferation, such as occurs in cancer, metastasis, arthritis and atherosclerosis.
  • Diseases of inappropriate repair include chronic diseases which have a remodeling or fibrotic component, such as renal fibrosis, chronic obstructive pulmonary disease, or idiopathic pulmonary fibrosis as a result of TGF-beta stimulation or other stimulation mediated by p38.
  • Inappropriate remodeling refers to excess deposition of collagen or other matrix components leading to loss of elasticity, tissue damage and scarring, and consequent impairment of tissue function.
  • treatment of stroke, neurotrauma, cardiac and renal reperfusion injury, congestive heart failure, coronary arterial bypass grafting (CABG) surgery, chronic renal failure, angiogenesis & related processes, such as cancer, thrombosis, glomerulonephritis, diabetes and pancreatic cells, multiple sclerosis, muscle degeneration, eczema, psoriasis, sunburn, and conjunctivitis are also included as treatable by inhibition of p38 MAP kinase by anti-inflammatory mechanisms.
  • P38 inhibitors are effective in many in vivo animal models of the complex diseases identified with an inflammatory component. P38 inhibitors are effective in models of arthritis such as the collagen-induced arthritis model, adjuvant arthritis model and PGPS model. Inhibition of TNF production in the endotoxic shock model. Where the reduction in plasma level of TNF correlated with survival and protection from endotoxic shock related mortality.
  • Inhibitors of p38 kinase activity are effective in inhibiting bone resorption in a rat fetal long bone organ culture system, in inhibition of indices of pain in models of neurogenic pain, in inhibition of pulmonary inflammation in models such as ozone-induced mucin production, LPS induced neutrophilia; in models of fibrosis such as bleomycin induced lung fibrosis or TGFbeta induced renal fibrosis.
  • These models represent specific aspects of the diseases identified in the preceding sections. Efficacy in these models are indicative of expected therapeutic efficacy on markers and disease states caused by stimuli that cause pathological activation of the p38 enzyme. [Griswold et al., (1988) Arthritis Rheum.
  • the compounds of Formula (I) may also be used topically in the treatment or prophylaxis of topical disease states mediated by or exacerbated by excessive cytokine production, such as by IL-1 or TNF respectively, such as inflamed joints, eczema, psoriasis and other inflammatory skin conditions such as sunburn; inflammatory eye conditions including conjunctivitis; pyresis, pain and other conditions associated with inflammation.
  • Periodontal disease has also been implicated in cytokine production, both topically and systemically.
  • topical treatment could include delivery to the lung of a compound of Formula (I) for treatment of pulmonary diseases such as COPD, chronic bronchitis, emphysema, idiopathic pulmonary fibrosis, or asthma.
  • the compounds of Formula (I) are administered in an amount sufficient to inhibit markers of inflammation such as cytokine or chemokine, in particular IL-1 , IL-6, IL-8 or TNF, production such that it is regulated down to therapeutically effective levels, which could be lower than the elevated disease levels, or as low as normal clinical levels, or in some cases to subnormal levels, so as to ameliorate or prevent the disease state.
  • markers of inflammation such as cytokine or chemokine, in particular IL-1 , IL-6, IL-8 or TNF
  • Abnormal or elevated levels of IL-1 , IL- 6, IL-8 or TNF constitute: (i) levels of free (not cell bound) IL-1 , IL-6, IL-8 or TNF greater than or equal to 1 picogram per ml; (ii) any cell associated IL-1 , IL-6, IL-8 or TNF; or (iii) the presence of IL-1 , IL-6, IL-8 or TNF mRNA above basal levels in cells or tissues in which IL-1 , IL-6, IL-8 or TNF, respectively, is produced.
  • the compounds of Formula (I) are inhibitors of cytokines, specifically IL-1 , IL-6, IL-8 and TNF is based upon the effects of the compounds of Formulas (I) on the production of the IL-1 , IL-8 and TNF in in vitro assays which are described herein.
  • TNF refers to: a) a decrease of excessive in vivo levels of the cytokine (IL-1 , IL-6, IL-8 or TNF) in a human to normal or sub-normal levels by inhibition of the in vivo release of the cytokine by cells, including but not limited to monocytes, macrophages, endothelial cells, or neutrophils; b) a down regulation, at the genomic level, of excessive in vivo levels of the cytokine (IL-1 , IL-6, IL-8 or TNF) in a human to normal or sub-normal levels; c) a down regulation, by inhibition of the direct synthesis of the cytokine (IL-1 , IL-6, IL-8 or TNF) as a postranslational event; or d) a down regulation, at the translational level, of excessive in vivo levels of the cytokine (IL-1 , IL-6, IL-8 or TNF) in a human to normal or sub-normal levels.
  • TNF mediated disease or disease state refers to any and all disease states in which TNF plays a role, either by production of TNF itself, or by TNF causing another monokine to be released, such as but not limited to IL-1 , IL-6 or IL-8.
  • TNF plays a role in disease such as stroke, for instance, through initiation of apoptosis of target cells, causing tissue damage. Reduction of TNF levels will also ameliorate the tissue damage.
  • cytokine refers to any secreted polypeptide that affects the functions of cells and is a molecule, which modulates interactions between cells in the immune, inflammatory or hematopoietic response.
  • a cytokine includes, but is not limited to, monokines and lymphokines, regardless of which cells produce them.
  • a monokine is generally referred to as being produced and secreted by a mononuclear cell, such as a macrophage and/or monocyte.
  • Lymphokines are generally referred to as being produced by lymphocyte cells.
  • cytokines include, but are not limited to, lnterleukin-1 (IL-1), lnterleukin-6 (IL-6), lnterleukin-8 (IL-8), Tumor Necrosis Factor-alpha (TNF- ⁇ ) and Tumor Necrosis Factor beta (TNF- ⁇ ).
  • cytokine interfering or "cytokine suppressive amount” refers to an effective amount of a compound of Formula (I) which will cause a decrease in the in vivo levels of the cytokine to normal or sub-normal levels, when given to a patient for the prophylaxis or treatment of a disease state which is exacerbated by, or caused by, excessive or unregulated cytokine production.
  • the cytokine referred to in the phrase "inhibition of a cytokine, for use in the treatment of a HIV-infected human” is a cytokine which is implicated in (a) the initiation and/or maintenance of T cell activation and/or activated T cell-mediated HIV gene expression and/or replication and/or (b) any cytokine-mediated disease associated problem such as cachexia or muscle degeneration.
  • TNF- ⁇ also known as lymphotoxin
  • TNF- ⁇ also known as cachectin
  • cachectin since each induces similar biologic responses and binds to the same cellular receptor, both TNF- ⁇ and TNF- ⁇ are inhibited by the compounds of the present invention and thus are herein referred to collectively as "TNF” unless specifically delineated otherwise.
  • the present invention provides a method of treating a p38 kinase mediated disease in a mammal in need thereof, preferably a human, which comprises administering to said mammal, an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • the compounds of Formula (I) may be used in combination with other therapeutically active ingredients. These combinations may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations comprising a combination as defined above together with a pharmaceutically acceptable carrier or excipient comprise a further aspect of the invention.
  • either the compound of the invention or the second therapeutic agent may be administered first.
  • the combination may be administered either in the same or different pharmaceutical composition.
  • the two compounds When combined in the same formulation it will be appreciated that the two compounds must be stable and compatible with each other and the other components of the formulation. When formulated separately they may be provided in any convenient formulation, conveniently in such manner as are known for such compounds in the art.
  • a compound of Formula (I) or a pharmaceutically acceptable salt thereof in therapy, it will normally be formulated into a pharmaceutical composition in accordance with standard pharmaceutical practice with regard to the intended route of administration and standard pharmaceutical practice.
  • This invention therefore, also relates to a pharmaceutical composition comprising an effective, non-toxic amount of a compound of Formula (I) and a pharmaceutically acceptable excipients, carrier or diluent.
  • Compounds of Formula (I), pharmaceutically acceptable salts thereof and pharmaceutical compositions incorporating such may conveniently be administered by any of the routes conventionally used for drug administration, for instance, orally, topically, parentally or by inhalation.
  • the compounds of Formula (I) may be administered in conventional dosage forms prepared by combining a compound of Formula (I) with standard pharmaceutical carriers according to conventional procedures.
  • the compounds of Formula (I) may also be administered in conventional dosages in combination with a known, second therapeutically active compound. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation. It will be appreciated that the form and character of the pharmaceutically acceptable character or diluent is dictated by the amount of active ingredient with which it is to be combined, the route of administration and other well-known variables.
  • the carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • the pharmaceutical compositions may be for human or animal usage in human and veterinary medicine and will typically comprise any one or more of a pharmaceutically acceptable excipient, diluent or carrier.
  • Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical art, and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaro edit. 1985).
  • the choice of pharmaceutical excipient, diluent or carrier can be selected with regard to the intended route of administration and standard pharmaceutical practice.
  • the pharmaceutical compositions may comprise, or in addition to, the excipient, diluent or carrier any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s) and solubilizing agent(s).
  • the pharmaceutical carrier employed may be, for example, either a solid or liquid.
  • solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like.
  • liquid carriers are syrup, peanut oil, olive oil, water and the like.
  • the carrier or diluent may include time delay material well known to the art, such as glyceryl mono-stearate or glyceryl distearate alone or with a wax.
  • the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form or in the form of a troche or lozenge.
  • the amount of solid carrier will vary widely but preferably will be from about 25mg. to about 1g.
  • the preparation will be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampule or nonaqueous liquid suspension.
  • the present invention includes pharmaceutical compositions containing
  • a compound of the formula (I) in combination with a pharmaceutically acceptable carrier.
  • Preservatives, stabilisers, dyes and even flavouring agents may be provided in the pharmaceutical composition.
  • preservatives include sodium benzoate, sorbic acid and esters of p-hydroxybenzoic acid.
  • Antioxidants and suspending agents may be also used.
  • the compounds of the invention may be milled using known milling procedures such as wet milling to obtain a particle size appropriate for tablet formation and for other formulation types. Finely divided (nanoparticulate) preparations of the compounds of the invention may be prepared by processes known in the art, for example see WO 02/00196 (SmithKline Beecham).
  • the pharmaceutical composition of the present invention may be formulated to be delivered using a mini-pump or by a mucosal route, for example, as a nasal spray or aerosol for inhalation or ingestible solution, or parenterally in which the composition is formulated by an injectable form, for delivery, by, for example, an intravenous, intramuscular or subcutaneous route.
  • the formulation may be designed to be delivered by both routes.
  • the agent is to be delivered mucosally through the gastrointestinal mucosa, it should be able to remain stable during transit though the gastrointestinal tract; for example, it should be resistant to proteolytic degradation, stable at acid pH and resistant to the detergent effects of bile.
  • the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form or in the form of a troche or lozenge.
  • the amount of solid carrier will vary widely but will generally be from about 25mg. to about 1g.
  • the preparation will be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampoule or nonaqueous liquid suspension.
  • the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like, or those as described above.
  • the tablets may also contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine, disintegrants such as starch (such as corn, wheat, potato or tapioca starch), sodium starch glycollate, croscarmellose sodium and certain complex silicates, and granulation binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC) 1 sucrose, gelatin and acacia.
  • lubricating agents such as magnesium or calcium stearate, stearic acid, glyceryl behenate and talc may be included.
  • Solid compositions of a similar type may also be employed as fillers in gelatin capsules.
  • Preferred excipients in this regard include lactose, starch, a cellulose, milk sugar or high molecular weight polyethylene glycols.
  • the agent may be combined with various sweetening or flavouring agents, colouring matter or dyes, with emulsifying and/or suspending agents and with diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof.
  • Powders are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol. Flavoring, preservative, dispersing and coloring agent can also be present.
  • Capsules can be made by preparing a powder mixture as described above, and filling formed gelatin sheaths.
  • Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate or solid polyethylene glycol can be added to the powder mixture before the filling operation.
  • a disintegrating or solubilizing agent such as agar-agar, calcium carbonate or sodium carbonate can also be added to improve the availability of the medicament when the capsule is ingested.
  • suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like.
  • Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
  • Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant and pressing into tablets.
  • a powder mixture is prepared by mixing the compound, suitably comminuted, with a diluent or base as described above, and optionally, with a binder such as carboxymethylcellulose, an alginate, gelatin, or polyvinyl pyrrolidone, a solution retardant such as paraffin, a resorption accelerator such as a quaternary salt and/or an absorption agent such as bentonite, kaolin or dicalcium phosphate.
  • a binder such as carboxymethylcellulose, an alginate, gelatin, or polyvinyl pyrrolidone
  • a solution retardant such as paraffin
  • a resorption accelerator such as a quaternary salt
  • an absorption agent such as bentonite, kaolin or dicalcium phosphate.
  • the powder mixture can be granulated by wetting with a binder such as syrup, starch paste, acacia mucilage or solutions of cellulosic or polymeric materials and forcing through a screen.
  • a binder such as syrup, starch paste, acacia mucilage or solutions of cellulosic or polymeric materials and forcing through a screen.
  • the powder mixture can be run through the tablet machine and the result is imperfectly formed slugs broken into granules.
  • the granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stearate salt, talc or mineral oil.
  • the lubricated mixture is then compressed into tablets.
  • the compounds of the present invention can also be combined with free flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps.
  • a clear or opaque protective coating consisting of a sealing coat of shellac, a coating of sugar or
  • compositions can be administered by inhalation, in the form of a suppository or pessary, topically in the form of a lotion, solution, cream, ointment or dusting powder, by use of a skin patch, orally in the form of tablets containing excipients such as starch or lactose, or in capsules or ovules either alone or in admixture with excipients, or in the form of elixirs, solutions or suspensions containing flavouring or colouring agents, or they can be injected parenterally, for example intravenously, intramuscularly or subcutaneously.
  • compositions may be best used in the form of a sterile aqueous solution which may contain other substances, for example enough salts or monosaccharides to make the solution isotonic with blood.
  • compositions may be administered in the form of tablets or lozenges which can be formulated in a conventional manner.
  • this can include topical applications externally to the epidermis or the buccal cavity, or the instillation of such a compound into the ear, eye and nose, or inhalation into the lung, such that the compound does not significantly enter the blood stream, or mucosal (e. g. as a nasal spray or aerosol for inhalation)
  • systemic administration refers to oral, parenteral (e.g. by injectable form, such as intravenous), intraperitoneal, intramuscular, and intraspinal administration.
  • Other routes of administration can include, but are not limited to, intrauterine, intraocular, intradermal, intracranial, intratracheal, intravaginal, intracerebroventricular, intracerebral, subcutaneous, ophthalmic (including intravitreal or intracameral), transdermal, rectal, epidural and sublingual. It is to be understood that not all of the compounds need be administered by the same route. Likewise, if the composition comprises more than one active component, then those components may be administered by different routes.
  • the compounds of formula (I) and their pharmaceutically acceptable salts and solvates may be formulated for administration in any suitable manner. They may, for example, be formulated for topical administration or administration by inhalation or, more preferably, for oral, transdermal or parenteral administration.
  • the pharmaceutical composition may be in a form such that it can affect controlled release of the compounds of formula (I) and their pharmaceutically acceptable derivatives.
  • the agents of the present invention are delivered via oral inhalation or intranasal administration. Appropriate dosage forms for such administration, such as an aerosol formulation or a metered dose inhaler, may be prepared by conventional techniques.
  • the compounds may be delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, a hydrofluoroalkane such as tetrafluoroethane or heptafluoropropane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, a hydrofluoroalkane such as tetrafluoroethane or heptafluoropropane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, a
  • gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of a compound of the invention and a suitable powder base such as lactose or starch.
  • Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site of inflammation such as liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose.
  • the active ingredient may comprise, for topical administration, from about 0.001 % to about 10% w/w, for instance from about 1 % to about 2% by weight of the formulation. It may however comprise as much as about 10% w/w but generally may comprise less than 5% w/w, or in another embodiment from about 0.1 % to about 1% w/w of the formulation.
  • Lotions according to the present invention include those suitable for application to the skin or eye.
  • An eye lotion may comprise a sterile aqueous solution optionally containing a bactericide and may be prepared by methods similar to those for the preparation of drops.
  • Lotions or liniments for application to the skin may also include an agent to hasten drying and to cool the skin, such as an alcohol or acetone, and/or a moisturizer such as glycerol or an oil such as castor oil or arachis oil.
  • Creams, ointments or pastes according to the present invention are semi- ⁇ solid formulations of the active ingredient for external application. They may be made by mixing the active ingredient in finely-divided or powdered form, alone or in solution or suspension in an aqueous or non-aqueous fluid, with the aid of suitable machinery, with a greasy or non-greasy base.
  • the base may comprise hydrocarbons such as hard, soft or liquid paraffin, glycerol, beeswax, a metallic soap; a mucilage; an oil of natural origin such as almond, corn, arachis, castor or olive oil; wool fat or its derivatives or a fatty acid such as stearic or oleic acid together with an alcohol such as propylene glycol or a macrogel.
  • the formulation may incorporate any suitable surface active agent such as an anionic, cationic or non-ionic surfactant such as a sorbitan ester or a polyoxyethylene derivative thereof.
  • Suspending agents such as natural gums, cellulose derivatives or inorganic materials such as silicaceous silicas, and other ingredients such as lanolin, may also be included.
  • Drops according to the present invention may comprise sterile aqueous or oily solutions or suspensions and may be prepared by dissolving the active ingredient in a suitable aqueous solution of a bactericidal and/or fungicidal agent and/or any other suitable preservative, and may include a surface active agent.
  • the resulting solution may then be clarified by filtration, transferred to a suitable container which is then sealed and sterilized by autoclaving or maintaining at 98- 100°C. for half an hour.
  • the solution may be sterilized by filtration and transferred to the container by an aseptic technique.
  • bactericidal and fungicidal agents suitable for inclusion in the drops are phenylmercuric nitrate or acetate (0.002%), benzalkonium chloride (0.01%) and chlorhexidine acetate (0.01%).
  • Suitable solvents for the preparation of an oily solution include glycerol, diluted alcohol and propylene glycol.
  • the daily oral dosage regimen will in one embodiment be from about 0.1 to about 80 mg/kg of total body weight; or from about 0.2 to 30 mg/kg, or from about 0.5 mg to 15mg.
  • the daily parenteral dosage regimen may be from about 0.1 to about 80 mg/kg of total body weight, or from about 0.2 to about 30 mg/kg, or from about 0.5 mg to 15mg/kg.
  • the daily topical dosage regimen in one embodiment may be from 0.1 mg to 150 mg, administered one to four, suitably from two or three times daily.
  • the daily inhalation dosage regimen will suitably be from about 0.001 mg/kg to about 1 mg/kg per day.
  • the optimal quantity and spacing of individual dosages of a compound of Formula (I) or a pharmaceutically acceptable salt thereof will be determined by the nature and extent of the condition being treated, the form, route and site of administration, and the particular patient being treated, and that such optimums can be determined by conventional techniques. It will also be appreciated by one of skill in the art that the optimal course of treatment, i.e., the number of doses of a compound of Formula (I) or a pharmaceutically acceptable salt thereof given per day for a defined number of days, can be ascertained by those skilled in the art using conventional course of treatment determination tests.
  • novel compounds of Formula (I) may also be used in association with the veterinary treatment of mammals, other than humans, in need of inhibition of CSBP/p38 or cytokine inhibition or production.
  • CSBP/p38 mediated diseases for treatment, therapeutically or prophylactically, in animals include disease states such as those noted herein in the Methods of Treatment section.
  • suitable viruses for treatment include, but are not limited to, lentivirus infections such as, equine infectious anaemia virus, caprine arthritis virus, visna virus, or maedi virus or retrovirus infections, such as but not limited to feline immunodeficiency virus (FIV), bovine immunodeficiency virus, or canine immunodeficiency virus or other retroviral infections.
  • the compound of the present invention can be administered in the form of a suppository or pessary, or it may be applied topically in the form of a gel, hydrogel, lotion, solution, cream, ointment or dusting powder.
  • the compounds of the present invention may also be administered by the pulmonary or rectal routes. They may also be administered by the ocular route.
  • the compounds can be formulated as micronised suspensions in isotonic, pH adjusted, sterile saline, or, preferably, as solutions in isotonic, pH adjusted, sterile saline, optionally in combination with a preservative such as a benzylalkonium chloride.
  • they may be formulated in an ointment such as petrolatum.
  • compositions generally are administered in an amount effective for treatment or prophylaxis of a specific condition or conditions. Initial dosing in humans is accompanied by clinical monitoring of symptoms, such symptoms for the selected condition.
  • BIOLOGICAL EXAMPLES The activity of compounds of formula (I) as p38 inhibitors may be determined by the following in vitro assays: Fluorescence anisotropy kinase binding assay
  • the kinase enzyme, fluorescent ligand and a variable concentration of test compound are incubated together to reach thermodynamic equilibrium under conditions such that in the absence of test compound the fluorescent ligand is significantly (>50%) enzyme bound and in the presence of a sufficient concentration (>10x Ki) of a potent inhibitor the anisotropy of the unbound fluorescent ligand is measurably different from the bound value.
  • the concentration of kinase enzyme should preferably be > 1 x K f .
  • the concentration of fluorescent ligand required will depend on the instrumentation used, and the fluorescent and physicochemical properties.
  • the concentration used must be lower than the concentration of kinase enzyme, and preferably less than half the kinase enzyme concentration.
  • Fluorescent ligand concentration 5 nM
  • Test compound concentration 0.1 nM - 100 uM
  • Components incubated in 30 ul final volume in NUNC 384 well black microtitre plate until equilibrium reached (5-30 mins) Fluorescence anisotropy read in LJL Acquest.
  • Kj dissociation constant for inhibitor binding
  • Kf dissociation constant for fluorescent ligand binding
  • the fluorescent ligand is the following compound:
  • Time-resolved fluorescence resonance energy transfer kinase assay Recombinant human p38 ⁇ was expressed as a His-tagged protein. To activate this protein, 3 ⁇ M unactivated p38 ⁇ was incubated in 20OmM Hepes pH7.4, 625mM NaCI, 1 mM DTT with 27 nM active MKK6 (Upstate), 1 mM ATP and 1OmM MgCI 2 The activity of the MKK6-activated p38 ⁇ was assessed using a time-resolved fluorescence resonance energy transfer (TR-FRET) assay.
  • TR-FRET time-resolved fluorescence resonance energy transfer
  • Biotinylated-GST-ATF2 (residues 19-96, 40OnM final), ATP (125M final) and MgCI2 (5mM final) in assay buffer (40 mM HEPES pH 7.4, 1 mM DTT) were added to wells containing 11 of various concentrations of compound or DMSO vehicle (3% final) in assay buffer (40 mM HEPES pH 7.4, 1 mM DTT) were added to wells containing 11 of various concentrations of compound or DMSO vehicle (3% final) in
  • NUNC 384 well black plate The reaction was initiated by the addition of MKK6-activated p38 (10OpM final) to give a total volume of 30 ⁇ . Alternatively, various concentrations of compound were incubated with activated p38 for up to 90 min, followed by initiation with the addition of ATF2, ATP and MgCI2. The reaction was incubated for 120 minutes at room temperature, then terminated by the addition of 15 ⁇ of 100 mM EDTA pH 7.4.
  • Detection reagent (15 /vl) in buffer (100 mM HEPES pH 7.4, 150 mM NaCI, 0.1 % w/v BSA, 1 mM DTT) containing antiphosphothreonine-ATF2-71 polyclonal antibody (Cell Signalling Technology, Beverly Massachusetts, USA) labelled with W-1024 europium chelate (Wallac OY, Turku, Finland), and APC-labelled streptavidin (Prozyme, San Leandro, California, USA) was added and the reaction was further incubated for 60 minutes at room temperature.
  • buffer 100 mM HEPES pH 7.4, 150 mM NaCI, 0.1 % w/v BSA, 1 mM DTT
  • antiphosphothreonine-ATF2-71 polyclonal antibody Cell Signalling Technology, Beverly Massachusetts, USA
  • W-1024 europium chelate W-1024 europium chelate
  • APC-labelled streptavidin Prozyme, San Leandro, California, USA
  • the degree of phosphorylation of GST-ATF2 was measured using a Packard Discovery plate reader (Perkin-Elmer Life Sciences, Pangbourne, UK) as a ratio of specific 665 nm energy transfer signal to reference europium 620 nm signal. Differences in IC50 with or without preincubation of enzyme with compound was interpreted as time-dependence.
  • Triethylamine (2.8 ml_, 20.4 mmol) was added to a fine suspension of A- bromoisophthalic acid (5.0 g, 20.4 mmol) in dichloromethane (150 ml_, HPLC grade) and the resultant reaction mixture was stirred for 30 min, at which point the mixture was completely homogenous.
  • ⁇ /, ⁇ /-Carbonyldiimidazole (5.5 g, 33.7 mmol) was added portionwise over 5 min, the mixture was stirred for 1 h, and then neopentylamine (2.4 ml_, 20.4 mmol) was added.
  • Oxalyl chloride (7.6 mL, 87.1 mmol) was added to a solution of 3-fluoro-5- iodo-4-methylbenzoic acid (20 g, 71.4 mmol) in tetrahydrofuran (100 mL) and a drop of ⁇ /, ⁇ /-dimethylformamide at 0 0 C, and the resultant reaction mixture was allowed to warm to room temperature over 1-2 h. The excess oxalyl chloride was removed under reduced pressure, tetrahydrofuran (100 mL) was added to the residue, the resultant solution was cooled to 0 0 C, and potassium te/t-butoxide (8.0 g, 71.3 mmol) was added.
  • Lithium hydroxide monohydrate (2.44 g, 58.3 mmol) was added portionwise, over 5 min, to a stirred solution of 3'-(1 ,1 -dimethylethyl) 2-methyl 4- ⁇ [(2,2-dimethylpropyl)amino]carbonyl ⁇ -5'-fluoro-6'-methyl-2,3'- biphenyldicarboxylate (5.33 g, 11.7 mmol) in tetrahydrofuran (50 ml_) at O 0 C, and the resultant reaction mixture was stirred at O 0 C for 5 min before water (25 ml_) was added and the mixture was allowed to warm to room temperature.
  • Benzotriazo-1 -yloxyths(pyrrolidino)phosphonium (4.0 g, 7.69 mmol) was added portionwise, over 5 min, to a stirred solution of 5'- ⁇ [(1 ,1- dimethylethyl)oxy]carbonyl ⁇ -4- ⁇ [(2,2-dimethylpropyl)amino]carbonyl ⁇ -3'-fluoro-2'- methyl-2-biphenylcarboxylic acid (1.5 g, 3.4 mmol), 2-aminothiazole (406 mg, 4.1 mmol), and H ⁇ nigs base (1.6 ml_, 10.2 mmol) in anhydrous N 1 N- dimethylformamide (23 ml_).
  • Aqueous hydrochloric acid (10 ml_ of a 20% solution) was added to a stirred solution of 1 ,1-dimethylethyl 4'- ⁇ [(2,2-dimethylpropyl)amino]carbonyl ⁇ -5- fluoro-6-methyl-2'-[(1 ,3-thiazol-2-ylamino)carbonyl]-3-biphenylcarboxylate (1.41 g, 2.68 mmol) in 1 ,4-dioxane (10 ml_), and the resultant cloudy mixture was heated at reflux for 30 min.
  • reaction mixture was extracted with dichloromethane (3 x 5 ml_) and the combined organic extracts were dried (MgSO 4 ) and concentrated under vacuum.
  • N- iodosuccinimide 58 g, 0.20mol
  • a final portion 35 g, 0.16 mol
  • the reaction mixture was then poured into a mixture of ice (2.3 kg) and 10% aqueous sodium thiosulphate (1.2 L) and allowed to warm to room temperature.
  • the resultant solid was collected by filtration, washed with water, air-dried, and taken up in ethyl acetate (4.0 L).
  • 2-Aminothiazole 25mg, 0.25 mmol was added in one portion to a stirred solution of 5'-[(cyclopropylamino)carbonyl]-3'-fluoro-2'-methyl-2-[(1 ,3-thiazol-2- ylamino)carbonyl]-4-biphenylcarboxylic acid (100 mg, 0.21 mmol), 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (87 mg, 0.455mmol), and 4-dimethylaminopyridine (10mg) in anhydrous dichloromethane (3 ml_) under an atmosphere of argon, and the resultant reaction mixture was stirred at room temperature for 16 h.
  • Cyclohexylamine (0.2 ml) and diisopropylethylamine (0.1 ml) were added to a stirred suspension of ⁇ '-KcyclopropylaminoJcarbonylJ-S'-fluoro ⁇ '-methyl ⁇ - [(I .S-thiazol ⁇ -ylaminoJcarbonylH-biphenylcarboxylic acid (100 mg, 0.21 mmol), 0(6-chlorobenzotriazol-1-yl)-A/,A/,/V,/V-tetramethyluronium hexafluoro- phosphate) (108mg, 0.26 mmol) in anhydrous dichloromethane (3 mL) under an atmosphere of argon, and the resultant reaction mixture was stirred at room temperature for 3 days.
  • Cyclopropanemethylamine (50mg) was added in one portion to a stirred solution of 5'-[(cyclopropylamino)carbonyl]-3'-fluoro-2 l -methyl-2-[(1 ,3-thiazol-2- ylamino)carbonyl]-4-biphenylcarboxylic acid (100 mg, 0.21 mmol), 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (90 mg, 0.455mmol), and 4-dimethylaminopyridine (10mg) in anhydrous dichloromethane (3 ml_) under an atmosphere of argon, and the resultant reaction mixture was stirred at room temperature for five days.
  • 2,2,2-Trifluoroethylamine 70mg was added in one portion to a stirred solution of 5'-[(cyclopropylamino)carbonyl]-3'-fluoro-2'-methyl-2-[(1 ,3-thiazol-2- ylamino)carbonyl]-4-biphenylcarboxylic acid (100 mg, 0.21 mmol), 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (90 mg, 0.455mmol), and 4-dimethylaminopyridine (10mg) in anhydrous dichloromethane (3 mL) under an atmosphere of argon, and the resultant reaction mixture was stirred at room temperature for five days.
  • Benzylamine (70mg) was added in one portion to a stirred solution of 5'- [(cyclopropylamino)carbonyl]-3'-fluoro-2'-methyl-2-[(1 ,3-thiazol-2- ylamino)carbonyl]-4-biphenylcarboxylic acid (100 mg, 0.21 mmol), 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (90 mg, 0.455mmol), and 4-dimethylaminopyridine (10mg) in anhydrous dichloromethane (3 mL) under an atmosphere of argon, and the resultant reaction mixture was stirred at room temperature for two weeks.
  • Cyclohexanemethylamine (60mg) was added in one portion to a stirred solution of 5'-[(cyclopropylamino)carbonyl]-3'-fluoro-2'-methyl-2-[(1 ,3-thiazol-2- ylamino)carbonyl]-4-biphenylcarboxylic acid (100 mg, 0.21 mmol), 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (90 mg, 0.455mmol), and 4-dimethylaminopyridine (10mg) in anhydrous dichloromethane (3 ml_) under an atmosphere of argon, and the resultant reaction mixture was stirred at room temperature for five days.
  • 3-(Dibutylamino)-1 -propylamine 60mg was added in one portion to a stirred solution of 5'-[(cyclopropylamino)carbonyl]-3 l -fluoro-2'-methyl-2-[(1 ,3- thiazol-2-ylamino)carbonyl]-4-biphenylcarboxylic acid (100 mg, 0.228 mmol), 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (90 mg, 0.46 mmol), and 4-dimethylaminopyridine (10mg) in anhydrous dichloromethane (3 ml_) under an atmosphere of argon, and the resultant reaction mixture was stirred at room temperature for five days.
  • ⁇ /, ⁇ /-2,2-Tetramethyl-1 ,3-propanediamine 60mg was added in one portion to a stirred solution of ⁇ '-KcyclopropylaminoJcarbonylJ-S'-fluoro ⁇ '-methyl- 2-[(1 ,3-thiazol-2-ylamino)carbonyl]-4-biphenylcarboxylic acid (100 mg, 0.228 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (90 mg, 0.46 mmol), and 4-dimethylaminopyridine (10mg) in anhydrous dichloromethane (3 mL) under an atmosphere of argon, and the resultant reaction mixture was stirred at room temperature for two weeks.
  • 3-Pentylamine (60mg) was added in one portion to a stirred solution of 5 1 - [(cyclopropylamino)carbonyl]-3'-fluoro-2'-methyl-2-[(1 ,3-thiazol-2- ylamino)carbonyl]-4-biphenylcarboxylic acid (100 mg, 0.21 mmol), 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (90 mg, 0.455mmol), and 4-dimethylaminopyridine (10mg) in anhydrous dichloromethane (3 ml_) under an atmosphere of argon, and the resultant reaction mixture was stirred at room temperature for five days.
  • 3,4-Dimethylbenzylamine 60mg was added in one portion to a stirred solution of 5'-[(cyclopropylamino)carbonyl]-3'-fluoro-2'-methyl-2-[(1 ,3-thiazol-2- ylamino)carbonyl]-4-biphenylcarboxylic acid (100 mg, 0.21 mmol), 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (90 mg, 0.455mmol), and 4-dimethylaminopyridine (10mg) in anhydrous dichloromethane (3 ml_) under an atmosphere of argon, and the resultant reaction mixture was stirred at room temperature for five days.
  • Methylamine hydrochloride (60mg) was added in one portion to a stirred solution of 5'-[(cyclopropylamino)carbonyl]-3'-fluoro-2'-methyl-2-[(1 ,3-thiazol-2- ylamino)carbonyl]-4-biphenylcarboxylic acid (100 mg, 0.228 mmol), 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (90 mg, 0.46 mmol), triethylamine (0.2ml) and 4-dimethylaminopyridine (10mg) in anhydrous dichloromethane (3 ml_) under an atmosphere of argon, and the resultant reaction mixture was stirred at room temperature for five days.
  • N-(2-Aminoethyl)pyrrolidine 60mg was added in one portion to a stirred solution of 5'-[(cyclopropylamino)carbonyl]-3'-fluoro-2'-methyl-2-[(1 ,3-thiazol-2- ylamino)carbonyl]-4-biphenylcarboxylic acid (100 mg, 0.21 mmol), 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (90 mg, 0.455mmol), and 4-dimethylaminopyridine (10mg) in anhydrous dichloromethane (3 ml_) under an atmosphere of argon, and the resultant reaction mixture was stirred at room temperature for two weeks.
  • Example 78 methyl 4-(r(2,2-dimethylpropyl)annino1carbonyl)-5'-(r(2- hvdroxyethvDaminoicarbonyll ⁇ '-methyl ⁇ -biphenylcarboxylate 78a) 4'-(r(2.2-dimethylpropyl)aminolcarbonyl)-6-methyl-2'-r(methyloxy)carbonyll- 3-biphenylcarboxylic acid
  • Trimethyl borate (35.9 mL, 0.321 moles, 2.0 eq) was then added dropwise and the resulting mixture left for 5 min (temperature maintained below O 0 C).
  • the rxn mix was then quenched with water (400 mL) and ethyl acetate (500 mL) added.
  • the layers were separated and water (100 mL) was added, after which it was basified with 2 M NaOH.
  • the layers were separated and the aqueous acidified with 2 M HCI, after which, a solid precipitate was collected by filtration and dried at the pump to yield the title compound (3.75 g).
  • To the organic layer was then added ethyl acetate (500 mL), and the precipitate was filtered*.

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Abstract

L'invention concerne de nouveaux composés de formule (I) ou des dérivés de ceux-ci acceptables sur le plan pharmaceutique, et leur utilisation en tant que produits pharmaceutiques, notamment en tant qu'inhibiteurs de kinase p38.
EP05857821A 2004-10-05 2005-10-05 Nouveaux composes Withdrawn EP1805132A4 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US61606504P 2004-10-05 2004-10-05
US71972905P 2005-09-22 2005-09-22
PCT/US2005/035743 WO2006110173A2 (fr) 2004-10-05 2005-10-05 Nouveaux composes

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EP1805132A2 true EP1805132A2 (fr) 2007-07-11
EP1805132A4 EP1805132A4 (fr) 2010-01-20

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EP2080750B1 (fr) 2006-11-02 2020-07-29 Mitsubishi Gas Chemical Company, Inc. Composition sensible aux rayonnements
JP5446118B2 (ja) * 2007-04-23 2014-03-19 三菱瓦斯化学株式会社 感放射線性組成物
EP1992344A1 (fr) 2007-05-18 2008-11-19 Institut Curie P38 alpha comme cible therapeutique pour les maladies associées á une mutation de FGFR3
RU2456266C1 (ru) * 2011-04-06 2012-07-20 Максим Эдуардович Запольский Производные 4,4'-бифениламидов, обладающие фармакологической активностью, и лекарственные средства на их основе
WO2016029216A2 (fr) * 2014-08-22 2016-02-25 Biocryst Pharmaceuticals, Inc. Procédé de production de dérivés d'amidine
CN113149902B (zh) * 2015-09-30 2022-11-22 石药集团中奇制药技术（石家庄）有限公司 苯甲酰胺类衍生物
CN114732910A (zh) 2017-10-05 2022-07-12 弗尔康医疗公司 P38激酶抑制剂降低dux4和下游基因表达以用于治疗fshd
US10342786B2 (en) 2017-10-05 2019-07-09 Fulcrum Therapeutics, Inc. P38 kinase inhibitors reduce DUX4 and downstream gene expression for the treatment of FSHD

Citations (6)

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Publication number Priority date Publication date Assignee Title
EP1078917A1 (fr) * 1998-02-17 2001-02-28 Ono Pharmaceutical Co., Ltd. Derives amidino utilises comme ingredients actifs et medicaments les contenant
US6376546B1 (en) * 1997-10-14 2002-04-23 Asahi Kasei Kabushiki Kaisha Biphenyl-5-alkanoic acid derivatives and use thereof
US6541505B1 (en) * 1998-12-24 2003-04-01 Aventis Pharmaceuticals Inc. Substituted (aminoiminomethyl or aminomethyl) benzoheteroaryl compounds
WO2003032980A1 (fr) * 2001-10-17 2003-04-24 Glaxo Group Limited Derives de 5'carbamoyl-1,1'-biphenyl-4-carboxamide et leur utilisation comme inhibiteurs de la kinase p38
WO2004089874A1 (fr) * 2003-04-09 2004-10-21 Smithkline Beecham Corporation Amide biphenyle carboxylique utilises en tant qu'inhibiteurs de la kinase p38
WO2004089876A1 (fr) * 2003-04-09 2004-10-21 Smithkline Beecham Corporation Derives d'amide biphenylcarboxylique utilises en tant qu'inhibiteurs de la kinase p38

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Publication number Priority date Publication date Assignee Title
ZA801680B (en) * 1979-04-03 1981-03-25 Fujisawa Pharmaceutical Co 2-imidazoline derivatives,process for the preparation thereof and the pharmaceutical composition of the same
GB0124928D0 (en) * 2001-10-17 2001-12-05 Glaxo Group Ltd Chemical compounds
GB0124941D0 (en) * 2001-10-17 2001-12-05 Glaxo Group Ltd Chemical compounds

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6376546B1 (en) * 1997-10-14 2002-04-23 Asahi Kasei Kabushiki Kaisha Biphenyl-5-alkanoic acid derivatives and use thereof
EP1078917A1 (fr) * 1998-02-17 2001-02-28 Ono Pharmaceutical Co., Ltd. Derives amidino utilises comme ingredients actifs et medicaments les contenant
US6541505B1 (en) * 1998-12-24 2003-04-01 Aventis Pharmaceuticals Inc. Substituted (aminoiminomethyl or aminomethyl) benzoheteroaryl compounds
WO2003032980A1 (fr) * 2001-10-17 2003-04-24 Glaxo Group Limited Derives de 5'carbamoyl-1,1'-biphenyl-4-carboxamide et leur utilisation comme inhibiteurs de la kinase p38
WO2004089874A1 (fr) * 2003-04-09 2004-10-21 Smithkline Beecham Corporation Amide biphenyle carboxylique utilises en tant qu'inhibiteurs de la kinase p38
WO2004089876A1 (fr) * 2003-04-09 2004-10-21 Smithkline Beecham Corporation Derives d'amide biphenylcarboxylique utilises en tant qu'inhibiteurs de la kinase p38

Non-Patent Citations (1)

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Title
See also references of WO2006110173A2 *

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TW200628153A (en) 2006-08-16
WO2006110173A2 (fr) 2006-10-19
WO2006110173A3 (fr) 2006-11-23
PE20060493A1 (es) 2006-09-03

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