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  • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
  • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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  • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
  • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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  • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
  • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
  • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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  • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
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  • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
  • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
  • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

• This invention relates to fluorinated di-aryl urea compounds compounds of formula(I):
• the compounds of the invention inhibit production of cytokines involved in inflammatory processes and are thus useful for treating diseases and pathological conditions involving inflammation such as chronic inflammatory disease.
• This invention also relates to processes for preparing these compounds and to pharmaceutical compositions comprising these compounds.
• Tumor necrosis factor and interleukin- 1 (IL-1) are important biological entities collectively referred to as proinflammatory cytokines which play a role in cytokine mediated diseases. These, along with several other related molecules, mediate the inflammatory response associated with the immunological recognition of infectious agents. The inflammatory response plays an important role in limiting and controlling pathogenic infections.
• Elevated levels of proinflammatory cytokines are also associated with a number of diseases of autoimmunity such as toxic shock syndrome, rheumatoid arthritis, osteoarthritis, diabetes and inflammatory bowel disease (Dinarello, C.A., et al, 1984, Rev. Infect. Disease 6:5 ). In these diseases, chronic elevation of inflammation exacerbates or causes much of the pathophysiology observed. For example, rheumatoid synovial tissue becomes invaded with inflammatory cells that result in destruction to cartilage and bone (Koch, A.E., et al, 1995, J. Invest. Med. 43: 28-38).
• cytokines may be involved in endothelial cell pathogenesis including restenosis after percutaneous transluminal coronary angioplasty (PTCA) (Tashiro, H., et al, 2001 Mar, Coron Artery Dis 12(2):101- 3).
• PTCA percutaneous transluminal coronary angioplasty
• An important and accepted therapeutic approach for potential drug intervention in these diseases is the reduction of proinflammatory cytokines such as TNF (also referred to in its secreted cell- free form as TNF ⁇ ) and IL-l ⁇ .
• TNF also referred to in its secreted cell- free form as TNF ⁇
• IL-l ⁇ IL-l ⁇
• Efficacy has been demonstrated with a monoclonal antibody directed against TNF ⁇ in a number of autoimmune diseases (Heath, P., "CDP571: An Engineered Human IgG4 Anti-TNF ⁇ Antibody” IBC Meeting on Cytokine Antagonists, Philadelphia, PA, April 24-5, 1997). These include the treatment of rheumatoid arthritis, Crohn's disease and ulcerative colitis (Rankin, E.C.C., et al., 1997, British J. Rheum. 35: 334-342 and Stack, W.A., et al., 1997, Lancet 349: 521-524).
• the monoclonal antibody is thought to function by binding to both soluble TNF ⁇ and to membrane bound TNF.
• a soluble TNF ⁇ receptor has been engineered that interacts with TNF ⁇ . The approach is similar to that described above for the monoclonal antibodies directed against TNF ⁇ ; both agents bind to soluble TNF ⁇ , thus reducing its concentration.
• Enbrel Immunex, Seattle, WA
• Another version of the TNF ⁇ receptor, Ro 45-2081 has demonstrated efficacy in various animal models of allergic lung inflammation and acute lung injury.
• Ro 45-2081 is a recombinant chimeric molecule constructed from the soluble 55 kDa human TNF receptor fused to the hinge region of the heavy chain IgGl gene and expressed in eukaryotic cells (Renzetti, et al, 991, lnflamm. Res. 46: S143).
• IL-1 has been implicated as an immunological effector molecule in a large number of disease processes.
• IL-1 receptor antagonist (IL-lra) had been examined in human clinical trials. Efficacy has been demonstrated for the treatment of rheumatoid arthritis (Antril, Amgen). In a phase III human clinical trial IL-lra reduced the mortality rate in patients with septic shock syndrome (Dinarello, 1995, Nutrution 11, 492). Osteoarthritis is a slow progressive disease characterized by destruction of the articular cartilage. IL-1 is detected in synovial fluid and in the cartilage matrix of osteoarthritic joints.
• Antagonists of IL-1 have been shown to dimmish the degradation of cartilage matrix components in a variety of experimental models of arthritis (Chevalier, 1997, Biomed Pharmacother. 51, 58).
• Nitric oxide (NO) is a mediator of cardiovascular homeostasis, neurotransmission and immune function; recently it has been shown to have important effects in the modulation of bone remodeling.
• Cytokines such as IL-1 and TNF are potent stimulators of NO production.
• NO is an important regulatory molecule in bone with effects on cells of the osteoblast and osteoclast lineage (Evans, et al, 1996, JBone Miner Res. 11, 300). The promotion of beta-cell destruction leading to insulin dependent diabetes mellitus shows dependence on IL-1.
• IL-1 can effect this process by controlling the level of both cyclooxygenase II and inducible nitric oxide synthetase expression (McDaniel et al, 1996, Proc Soc Exp Biol Med. 211, 24). Inhibitors of cytokine production are expected to block inducible cyclooxygenase (COX- 2) expression. COX-2 expression has been shown to be increased by cytokines and it is believed to be the isoform of cyclooxygenase responsible for inflammation (M.K. O'Banion et al, Proc. Natl. Aead. Sci.
• cytokines such as IL-1
• COX inhibitors such as the familiar NSAIDs.
• IBD active inflammatory bowel disease
• a mucosal imbalance of intestinal IL-1 and IL-lra is present in patients with IBD. Insufficient production of endogenous IL-lra may contribute to the pathogenesis of IBD (Cominelli, et al, 1996, Aliment Pharmacol Ther. 10, 49).
• Alzheimer disease is characterized by the presence of beta-amyloid protein deposits, neurofibrillary tangles and cholinergic dysfunction throughout the hippocampal region. The structural and metabolic damage found in Alzheimer disease is possibly due to a sustained elevation of IL-1 (Holden, et al, 1995, Med Hypotheses, 45, 559).
• IL-1 A role for IL-1 in the pathogenesis of human immunodeficiency virus (HIV) has been identified.
• HIV human immunodeficiency virus
• IL-lra showed a clear relationship to acute inflammatory events as well as to the different disease stages in the pathophysiology of HIV infection (Kreuzer, et al, 1997, Clin Exp Immunol 109, 54).
• IL-1 and TNF are both involved in periodontal disease. The destructive process associated with periodontal disease may be due to a disregulation of both IL-1 and TNF (Howells, 1995, OralDis. 1, 266).
• TNF ⁇ and IL-1 ⁇ are also important mediators of septic shock and associated cardiopulmonary dysfunction, acute respiratory distress syndrome (ARDS) and multiple organ failure.
• ARDS acute respiratory distress syndrome
• TNF ⁇ and IL-6 levels have also been implicated in cachexia and muscle degradation, associated with HIV infection
• TNF ⁇ production HU-211
• Atherosclerosis is known to have an inflammatory component and cytokines such as IL-1 and TNF have been suggested to promote the disease.
• cytokines such as IL-1 and TNF have been suggested to promote the disease.
• an IL-1 receptor antagonist was shown to inhibit fatty streak formation (Elhage et al, 1998, Circulation, 97, 242).
• TNF ⁇ levels are elevated in airways of patients with chronic obstructive pulmonary disease and it may contribute to the pathogenesis of this disease (M.A. Higham et al, 2000, Eur. Respiratory J, 15, 281). Circulating TNF ⁇ may also contribute to weight loss associated with this disease (N. Takabatake et al, 2000, Amer. J. Resp. & Crit. Care Med., 161 (4 Pt 1), 1179). Elevated TNF ⁇ levels have also been found to be associated with congestive heart failure and the level has been correlated with severity of the disease (A.M. Feldman et al, 2000, J. Amer. College of Cardiology, 35, 537).
• TNF ⁇ has been implicated in reperfusion injury in lung (Borjesson et al, 2000, Amer. J. Physiol, 278, L3-12), kidney (Lemay et al, 2000, Transplantation, 69, 959), and the nervous system (Mitsui et al, 1999, Brain Res., 844, 192).
• TNF ⁇ is also a potent osteoclastogenic agent and is involved in bone resorption and diseases involving bone resorption (Abu-Amer et al, 2000, J. Biol. Chem., 275, 27307). It has also been found highly expressed in chondrocytes of patients with traumatic arthritis (Melchiorri et al, 2000, Arthritis and Rheumatism, 41, 2165). TNF ⁇ has also been shown to play a key role in the development of glomerulonephritis (Le Hir et al, 1998, Laboratory Investigation, 78, 1625).
• iNOS inducible nitric oxide synthetase
• IL-1 has also been shown to induce uveitis in rats which could be inhibited with IL-1 blockers.
• Cytokines including IL-1, TNF and GM-CSF have been shown to stimulate proliferation of acute myelogenous leukemia blasts (Bruserud, 1996, Leukemia Res. 20, 65).
• IL-1 was shown to be essential for the development of both irritant and allergic contact dermatitis. Epicutaneous sensitization can be prevented by the administration of an anti- LL-1 monoclonal antibody before epicutaneous application of an allergen (Muller, et al, 1996, Am J Contact Dermat. 7, 177).
• IL-1 knock out mice Data obtained from IL-1 knock out mice indicates the critical involvement in fever for this cytokine (Kluger et al, 1998, Clin Exp Pharmacol Physiol. 25, 141).
• a variety of cytokines including TNF, IL-1, IL-6 and IL-8 initiate the acute-phase reaction which is stereotyped in fever, malaise, myalgia, headaches, cellular hypermetabolism and multiple endocrine and enzyme responses (Beisel, 1995, Am J Clin Nntr. 62, 813).
• the production of these inflammatory cytokines rapidly follows trauma or pathogenic organism invasion.
• IL-8 correlates with influx of neutrophils into sites of inflammation or injury. Blocking antibodies against IL-8 have demonstrated a role for IL-8 in the neutrophil associated tissue injury in acute inflammation (Harada et ⁇ l, 1996, Molecular Medicine Today 2, 482).
• an inhibitor of IL-8 production may be useful in the treatment of diseases mediated predominantly by neutrophils such as stroke and myocardial infarction, alone or following thrombolytic therapy, thermal injury, adult respiratory distress syndrome (ARDS), multiple organ injury secondary to trauma, acute glomerulonephritis, dermatoses with acute inflammatory components, acute purulent meningitis or other central nervous system disorders, hemodialysis, leukopherisis, granulocyte transfusion associated syndromes, and necrotizing enterocolitis.
• Rhino virus triggers the production of various proinflammatory cytokines, predominantly IL-8, which results in symptomatic illnesses such as acute rhinitis (Winther et al, 1998, Am JRhinol 12, 17).
• IL-8 diseases that are effected by IL-8 include myocardial ischemia and reperfusion, inflammatory bowel disease and many others.
• IL-6 The proinflammatory cytokine IL-6 has been implicated with the acute phase response.
• IL-6 is a growth factor in a number in oncological diseases including multiple myeloma and related plasma cell dyscrasias (Treon, et al, 1998, Current Opinion in Hematology 5: 42). It has also been shown to be an important mediator of inflammation within the central nervous system. Elevated levels of IL-6 are found in several neurological disorders including AIDS dementia complex, Alzheimer's disease, multiple sclerosis, systemic lupus erythematosus, CNS trauma and viral and bacterial meningitis (Gruol, et al, 1997, Molecular Neurobiology 15: 307). IL-6 also plays a significant role in osteoporosis.
• cytokine differences such as IL-6 levels, exist in vivo between osteoclasts of normal bone and bone from patients with Paget's disease (Mills, et al, 1991, Calcif Tissue Int. 61, 16).
• a number of cytokines have been shown to be involved in cancer cachexia. The severity of key parameters of cachexia can be reduced by treatment with anti IL-6 antibodies or with IL-6 receptor antagonists (Strassmann, et al, 1995, Cytokins Mol Ther. 1, 107).
• IL-6 and IFN alpha are infectious diseases, such as influenza.
• Overexpression of IL-6 has been implicated in the pathology of a number of diseases including multiple myeloma, rheumatoid arthritis, Castleman's disease, psoriasis and post-menopausal osteoporosis (Simpson, et al, 1991, Protein Sci. 6, 929).
• Compounds that interfered with the production of cytokines including IL-6, and TNF were effective in blocking a passive cutaneous anaphylaxis in mice (Scholz et al, 1998, J. Med.
• GM-CSF is another proinflammatory cytokine with relevance to a number of therapeutic diseases. It influences not only proliferation and differentiation of stem cells but also regulates several other cells involved in acute and chronic inflammation. Treatment with GM-CSF has been attempted in a number of disease states including burn- ound healing, skin-graft resolution as well as cytostatic and radiotherapy induced mucositis (Masucci, 1996, Medical Oncology 13: 149). GM-CSF also appears to play a role in the replication of human immunodeficiency virus (HIV) in cells of macrophage lineage with relevance to AIDS therapy (Crowe et al, 1997, Journal of Leukocyte Biology 62, 41). Bronchial asthma is characterised by an inflammatory process in lungs. Involved cytokines include GM-CSF amongst others (Lee, 1998, JR Coll Physicians Lond 32, 56).
• HIV human immunodeficiency virus
• Interferon ⁇ has been implicated in a number of diseases. It has been associated with increased collagen deposition that is a central histopathological feature of graft- versus-host disease (Parkman, 1998, Curr Opin Hematol 5, 22). Following kidney transplantation, a patient was diagnosed with acute myelogenous leukemia. Retrospective analysis of peripheral blood cytokines revealed elevated levels of GM-CSF and LFN ⁇ . These elevated levels coincided with a rise in peripheral blood white cell count (Burke, et al, 1995, Leuk Lymphoma. 19, 173).
• IFN ⁇ insulin- dependent diabetes
• MS multiple sclerosis
• AIDS dementia complex Alzheimer's disease complex
• cytokines such as TNF, IL-1 and TEN ⁇ . These cytokines are thought to be involved in promoting apoptosis or programmed cell death of the surrounding vascular smooth muscle cells resulting in the atherosclerotic lesions (Geng, 1997, Hea t Vessels Suppl 12, 16). Allergic subjects produce mRNA specific for TEN ⁇ following challenge with Vespula venom (Bonay, et al., 1991, Clin Exp Immunol 109, 342).
• cytokines including IFN ⁇ has been shown to increase following a delayed type hypersensitivity reaction thus indicating a role for IFN ⁇ in atopic dermatitis (Szepietowski, et al, 1997, BrJDermatol. 137, 195). Histopathologic and immunohistologic studies were performed in cases of fatal cerebral malaria. Evidence for elevated IFN ⁇ amongst other cytokines was observed indicating a role in this disease (Udomsangpetch et al, 1997, Am JTrop MedHyg. 57, 501). The importance of free radical species in the pathogenesis of various infectious diseases has been established.
• the nitric oxide synthesis pathway is activated in response to infection with certain viruses via the induction of proinflammatory cytokines such as IFN ⁇ (Akaike, et al, 1998, Proc Soc Exp Biol Med. 217, 64).
• proinflammatory cytokines such as IFN ⁇
• Patients, chronically infected with hepatitis B virus (HBV) can develop cirrhosis and hepatocellular carcinoma.
• Viral gene expression and replication in HBV transgenic mice can be suppressed by a post-transcriptional mechanism mediated by IFN ⁇ , TNF and IL-2 (Chisari, et al, 1995, Springer Semin Immunopathol 17, 261).
• IFN ⁇ can selectively inhibit cytokine induced bone resorption.
• NO nitric oxide
• NO is an important vasodilator and convincing evidence exists for its role in cardiovascular shock (Kilbourn, et al, 1997, Dis Mon. 43, 277).
• IFN ⁇ is required for progression of chronic intestinal inflammation in such diseases as Crohn's disease and inflammatory bowel disease (IBD) presumably through the intermediacy of CD4+ lymphocytes probably of the TH1 phenotype (Sartor 1996, Aliment Pharmacol Ther. 10 Suppl 2, 43).
• An elevated level of serum IgE is associated with various atopic diseases such as bronchial asthma and atopic dermatitis.
• WO 01/01986 discloses particular compounds alleged to having the ability to inhibit TNF-alpha.
• Certain compounds disclosed in WO 01/01986 are indicated to be effective in treating the following diseases: dementia associated with HIV infection, glaucoma, optic- neuropathy, optic neuritis, retinal ischemia, laser induced optic damage, surgery or trauma-induced proliferative vitreoretinopathy, cerebral ischemia, hypoxia-ischemia, hypoglycemia, domoic acid poisoning, anoxia, carbon monoxide or manganese or cyanide poisoning, Huntington's disease, Alzheimer's disease, Parkinson's disease, meningitis, multiple sclerosis and other demyelinating diseases, amyotrophic lateral sclerosis, head and spinal cord trauma, seizures, convulsions, olivopontocerebellar atrophy, neuropathic pain syndromes, diabetic neuropathy, HlN-related neuropathy, MERRF and MELAS syndromes, Leber's disease, Wernicke's encephalophathy, Reft syndrome, homocysteinuria, hyperprolinemia, hyperhom
• WO 02/32862 discloses that inhibitors of pro-inflammatory cytokines including T ⁇ F ⁇ are allegedly useful for treating acute and chronic inflammation in the lung caused by inhalation of smoke such as cigarette smoke.
• T ⁇ F ⁇ anatagonists are apparently also useful for the treatment of endometriosis, see EP 1022027 Al .
• Infliximab in clinical trials for RA, has also been indicated to be useful for treating various inflammatory diseases including Behcet's disease, uveitis and ankylosing spondylitis. Pancreatitis may also be regulated by inflammatory mediator production, see J Surg Res 2000 May 15 90(2)95-101; Shock 1998 Sep. 10(3):160-75.
• p38MAPkinase pathway plays an role in B.burgdorferi-elicited infammation and may be useful in treating inflammation induced by the Lyme disease agent.
• WO 98/52558 discloses heteroaryl urea compounds which are indicated to be useful in treating cytokine mediated diseases.
• WO 99/23091 discloses another class of urea compounds which are useful as anti-inflammatory agents.
• WO 99/32463 relates to aryl ureas amd their use in treating cytokine diseases and proteolytic enzyme mediated disease.
• WO 00/41698 discloses aryl ureas said to be useful in treating p38 MAP kinase diseases.
• U.S. Pat. No. 5,162,360 discloses N-substituted aryl-N'-heterocyclic substituted urea compounds which are described as being useful for treating hypercholesterolemia and atheroclerosis.
• Di-substituted aryl and heteroaryl compounds are also disclosed in US Pat. Nos. 6,080,763; 6,319,921; 6,297,381 and 6,358,945.
• the compounds in the patents are alleged to possess anti-cytokine activity and are therefore useful in treating diseases associated with inflammation.
• WO 01/36403 discloses heteroaryl urea compounds useful for treating cytokine mediated diseases. Certain example compounds possess fluorinated alkyl and cycloalkyl substituted phenyl moities at the 3-urea position, and other distinct compounds possess substituted pyrimidinyloxynaphthyl moities at the 1-urea position.
• the compounds in the present application disclosed herein below differ structurally and by possessing a better combination of desirable properties: phamacokinetics, potency and selectivity for p38 MAP kinase.
• Rx is -CF 3 , -CH(CH 3 )(CF 3 ), -CH(CF 3 ) 2 , -OCF 3 , -CF 2 CF 3 ;
• R 2 is C ⁇ -5 alkyl
• R 3 is attached at the 3- or 4-position on the phenyl ring and is hydrogen, -NH 2 or R 4 - S(O) 2 -NH- wherein R 4 is chosen from C ⁇ _ 5 alkyl or carbocycle;
• W is CH or an N atom
• X is chosen from
• Cl-5 alkyl or Cl-5 alkoxy each optionally substituted by mono- or di-Cl-3 alkyl amino, morpholinyl, piperazinyl, pyrrolidinyl, triazolyl, imidazolyl or piperadinyl each ring being further optionally substituted with Cl-3 alkyl;
• R a is independently chosen from hydrogen, Cl-5 alkyl, aryl, arylCl-3 alkyl, C3-7cycloalkyl, C3-7cycloalkyl Cl-3 alkyl, Cl-5alkoxyCl-5alkyl and heterocyclyl Cl-3 alkyl wherein the heterocycyl is chosen from tetrahydrofuran, pyrrolidinyl and morpholinyl, each R a where possible is optionally substituted by one to two Cl-5 alkyl, Cl-5 alkoxy, hydroxy, halogen or amino optionally mono- or di- substituted by Cl-3 alkyl;
• R 2 is C 1- alkyl
• W is an N atom
• X is chosen from
• Cl-5 alkyl or Cl-5 alkoxy each optionally substituted by mono- or di-Cl-3 alkyl amino, morpholinyl, piperazinyl, pyrrolidinyl, triazolyl, imidazolyl or piperadinyl each ring being further optionally substituted with Cl-3 alkyl;
• R a is independently chosen from hydrogen, Cl-5 alkyl, phenylCl-3 alkyl, C3-6cycloalkyl, C3-6cycloalkyl Cl-3 alkyl, Cl-3alkoxyCl-3alkyl and heterocyclyl Cl-3 alkyl wherein the heterocycyl is chosen from tetrahydrofuran, pyrrolidinyl and morpholinyl, each R a where possible is optionally substituted by one to two Cl-3 alkyl, Cl-3 alkoxy, hydroxy, halogen or amino optionally mono- or di- substituted by C 1-2 alkyl.
• Ri is -CF 3 , -CH(CH 3 )(CF 3 ), -CH(CF 3 ) 2 or -CF 2 CF 3 ;
• R 2 is C 1-2 alkyl.
• the invention provides the following compounds:
• the invention also relates to the use of a compound of formula (I), wherein Ri, R 2 , R 3 , W and X have the meaning indicated, for preparing a pharmaceutical composition for the treatment and/or prevention of a cytokine mediated disease or condition..
• the invention also relates to pharmaceutical preparations, containing as active substance one or more compounds of general formula (I), wherein Ri, R 2 , R 3 , and X have the meanings indicated, or the pharmaceutically acceptable derivatives thereof, optionally combined with conventional excipients and/or carriers.
• the invention includes the use of any compounds of described above containing one or more asymmetric carbon atoms may occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. AU such isomeric forms of these compounds are expressly included in the present mvention.
• Each stereogenic carbon may be in the R or S configuration, or a combination of configurations.
• Some of the compounds of formula (I) can exist in more than one tautomeric form.
• the invention includes methods using all such tautomers.
• Cl-3 alkoxy is a Cl-3(not an example used) alkyl with a terminal oxygen, such as methoxy, ethoxy, propoxy.
• All alkyl, alkenyl and alkynyl groups shall be understood as being branched or unbranched where structurally possible and unless otherwise specified. Other more specific definitions are as follows:
• Carbocycles include hydrocarbon rings containing from three to ten carbon atoms. These carbocycles may be either aromatic and non-aromatic ring systems. The non-aromatic ring systems may be mono- or polyunsaturated. Preferred carbocycles include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptanyl, cycloheptenyl, phenyl, indanyl, indenyl, benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl, naphthyl, decahydronaphthyl, benzocycloheptanyl and benzocycloheptenyl. Certain terms for cycloalkyl such as cyclobutanyl and cyclobutyl shall be used inerchangeably.
• heteroatoms may replace either terminal carbon atoms or internal carbon atoms within a branched or unbranched carbon chain.
• groups can be substituted as herein above described by groups such as oxo to result in defmtions such as but not limited to: alkoxycarbonyl, acyl, amido and thioxo.
• Each aryl or heterocycle unless otherwise specified includes it's partially hydrogenated derivative.
• pyrrolidinyl may include pyrrolinyl
• phenyl may include it's hydrogenated derivatives such as cyclohexenyl.
• Other partially or fully hydrogenated derivatives will be apparent to one of ordinary skill in the art.
• nitrogen and sulfur include any oxidized form of nitrogen and sulfur and the quaternized form of any basic nitrogen.
• halogen as used in the present specification shall be understood to mean bromine, chlorine, fluorine or iodine, preferably fluorine.
• the compounds of the invention are only those which are contemplated to be 'chemically stable' as will be appreciated by those skilled in the art.
• a compound which would have a 'dangling valency', or a 'carbanion' are not compounds contemplated by the inventive methods disclosed herein.
• the invention includes pharmaceutically acceptable derivatives of compounds of formula (I).
• a "pharmaceutically acceptable derivative” refers to any pharmaceutically acceptable salt or ester, or any other compound which, upon administration to a patient, is capable of providing (directly or indirectly) a compound useful for the invention, or a pharmacologically active metabolite or pharmacologically active residue thereof.
• a pharmacologically active metabolite shall be understood to mean any compound of the invention capable of being metabolized enzymatically or chemically. This includes, for example, hydroxylated or oxidized derivative compounds of the formula (I).
• Pharmaceutically acceptable salts include those derived from pharmaceutically acceptable inorganic and organic acids and bases.
• suitable acids include hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p-sulfuric, tartaric, acetic, citric, methanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfuric and benzenesulfonic acids.
• Other acids such as oxalic acid, while not themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds and their pharmaceutically acceptable acid addition salts.
• prodrugs of compounds of the formula (I) include those compounds that, upon simple chemical transformation, are modified to produce compounds of the invention. Simple chemical transformations include hydrolysis, oxidation and reduction. Specifically, when a prodrug is administered to a patient, the prodrug may be transformed into a compound disclosed hereinabove, thereby imparting the desired pharmacological effect.
• the compounds disclosed therein effectively block inflammatory cytokine production from cells.
• the inhibition of cytokine production is an attractive means for preventing and treating a variety of cytokine mediated diseases or conditions associated with excess cytokine production, e.g., diseases and pathological conditions involving inflammation.
• the compounds are useful for the treatment of diseases and conditions as described in the Background section, including the following conditions and diseases: osteoarthritis, atherosclerosis, contact dermatitis, bone resorption diseases, reperfusion injury, asthma, multiple sclerosis, Guillain-Barre syndrome, Crohn's disease, ulcerative colitis, psoriasis, graft versus host disease, systemic lupus erythematosus and insulin- dependent diabetes mellitus, rheumatoid arthritis, toxic shock syndrome, Alzheimer's disease, toxic shock syndrome, diabetes, inflammatory bowel diseases, acute and chronic pain as well as symptoms of inflammation and cardiovascular disease, stroke, myocardial infarction, alone or following thrombolytic therapy, thermal injury, adult respiratory distress syndrome (ARDS), multiple organ injury secondary to trauma, acute glomerulonephritis, dermatoses with acute inflammatory components, acute purulent meningitis or other central nervous system disorders, syndromes associated with hemodialysis, leukopherisis, granul
• the compounds may be administered in any conventional dosage form in any conventional manner.
• Routes of administration include, but are not limited to, intravenously, intramuscularly, subcutaneously, intrasynovially, by infusion, sublingually, transdermally, orally, topically or by inhalation.
• the preferred modes of administration are oral and intravenous.
• the compounds may be administered alone or in combination with adjuvants that enhance stability of the inhibitors, facilitate administration of pharmaceutic compositions containing them in certain embodiments, provide increased dissolution or dispersion, increase inhibitory activity, provide adjunct therapy, and the like, including other active ingredients.
• combination therapies utilize lower dosages of the conventional therapeutics, thus avoiding possible toxicity and adverse side effects incurred when those agents are used as monotherapies.
• the above described compounds may be physically combined with the conventional therapeutics or other adjuvants into a single pharmaceutical composition. Reference is this regard may be made to Cappola et al.: US patent application no. 09/902,822, PCT/US 01/21860 and US provisional application no. 60/313,527, each incorporated by reference herein in their entirety.
• the compounds may then be administered together in a single dosage form.
• the pharmaceutical compositions comprising such combinations of compounds contain at least about 5%, but more preferably at least about 20%, of a compound of formula (I) (w/w) or a combination thereof.
• the optimum percentage (w/w) of a compound of the invention may vary and is within the purview of those skilled in the art.
• the compounds may be administered separately (either serially or in parallel). Separate dosing allows for greater flexibility in the dosing regime.
• dosage forms of the compounds described herein include pharmaceutically acceptable carriers and adjuvants known to those of ordinary skill in the art.
• carriers and adjuvants include, for example, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, buffer substances, water, salts or electrolytes and cellulose-based substances.
• Preferred dosage forms include, tablet, capsule, caplet, liquid, solution, suspension, emulsion, lozenges, syrup, reconstitutable powder, granule, suppository and transdermal patch. Methods for preparing such dosage forms are known (see, for example, H.C. Ansel and N.G.
• Dosage levels and requirements are well-recognized in the art and may be selected by those of ordinary skill in the art from available methods and techniques suitable for a particular patient. In some embodiments, dosage levels range from about 1-1000 mg/dose for a 70 kg patient. Although one dose per day may be sufficient, up to 5 doses per day may be given. For oral doses, up to 2000 mg/day may be required. Reference in this regard may also be made to US provisional application no. 60/339,249. As the skilled artisan will appreciate, lower or higher doses may be required depending on particular factors. For instance, specific dosage and treatment regimens will depend on factors such as the patient's general health profile, the severity and course of the patient's disorder or disposition thereto, and the judgment of the treating physician.
• the invention additionally provides for methods of making the compounds of the formula (I).
• the compounds of the invention and the intermediates in the scheme below may be prepared by the general methods and examples presented below, and methods known to those of ordinary skill in the art. Further reference in this regard may be made to US Pat. no. 6,297,381, US application nos. 09/505,582, 09/484,638, 09/735,160, 09/902,085, 09/698,442, 09/834,797, 09/611 , 109, 10/147,675, US provisional application nos. 60/206,327, 60/216,283, 60/295,909, 60/291,425, 60/283,642 and 60/268,841. Each of the aforementioned are incorporated herein by reference in their entirety.
• Method A a mixture of an arylamine of formula Ila and an arylisocyanate of formula III is dissolved in a non-protic, anhydrous solvent such as THF, ether, toluene, dioxane or ethyl acetate.
• a non-protic, anhydrous solvent such as THF, ether, toluene, dioxane or ethyl acetate.
• the preferred solvent is THF.
• the mixture is stirred at between 0 - 45° C, preferably at 25° C, for 2-24 h, and the volatiles are removed.
• Purification of the residue can be accomplished by recrystallization from an appropriate solvent such as ethyl acetate/hexanes, ethyl acetate/methanol, THF/petroleum ether or ethanol/water or by silica gel chromatography, using for example, hexanes and ethyl acetate as eluents, providing the product of formula I or precursors thereof.
• an appropriate solvent such as ethyl acetate/hexanes, ethyl acetate/methanol, THF/petroleum ether or ethanol/water
• silica gel chromatography using for example, hexanes and ethyl acetate as eluents, providing the product of formula I or precursors thereof.
• an arylamine of formula Ila is dissolved in a halogenated solvent, such as dichloromethane, chloroform or dichloroethane.
• a halogenated solvent such as dichloromethane, chloroform or dichloroethane.
• the preferred solvent is dichloromethane.
• the mixture is diluted with aqueous alkali, such as sodium bicarbonate or potassium carbonate, cooled in an ice hath and phosgene is added. The mixture is vigorously stirred for 5 - 40 min.
• the organic layer is dried, with agents such as MgSO 4 or Na 2 SO 4 , and the volatiles removed to provide the corresponding isocyanate.
• the isocyanate and arylamine IV are mixed in a non-protic, anhydrous solvent such as THF, ether, toluene, dioxane, dichloromethane or ethyl acetate.
• a non-protic, anhydrous solvent such as THF, ether, toluene, dioxane, dichloromethane or ethyl acetate.
• the preferred solvent is THF.
• the mixture is stirred at between about 0 - 45° C, preferably at 25° C, for 2 - 24 h, and the volatiles are removed. Purification of the residue by recrystallization or by silica gel chromatography, as above, provides the product of formula I or precursors thereof.
• an arylamine of formula Ila is dissolved in a suitable halogenated solvent such as dichloromethane, chloroform or dichloroethane.
• a suitable halogenated solvent such as dichloromethane, chloroform or dichloroethane.
• the preferred solvent is dichloromethane.
• a suitable base such as triethylamine may be added, followed by an alkyl or aryl chloroformate, such as t-butyl chloroformate or phenyl chloroformate (shown).
• the mixture is stirred at between 0 - 85° C, preferably at reflux temperature, for 2 - 24 h, and the volatiles are removed providing carbamate V.
• the carbamate and arylamine IV are mixed in a non-protic, anhydrous solvent such as THF, ether, toluene, dioxane, dichloromethane or ethyl acetate.
• a non-protic, anhydrous solvent such as THF, ether, toluene, dioxane, dichloromethane or ethyl acetate.
• the preferred solvent is THF.
• the mixture is stirred at between 0 - 110 °C, preferably at reflux temperature, for 2 - 24 h, and the volatiles are removed. Purification of the residue as above provides the product of formula I or precursors thereof.
• Method D an aromatic carboxylic acid is dissolved in a non-protic solvent, such as THF or diethyl ether, and an inorganic base, such as triethyl amine is added and the mixture is cooled to -30-0°C, with the preferred temperature being -10°C.
• An alkyl chloroformate such as ethyl chloroformate, is added dropwise and the resulting mixture stirred at below room temperature, such as 0°C for 1-3 hours.
• a solution of sodium azide in water is added and the mixtiure stirred between 1-3 hours, diluted with toluene and the organic layer dried and reduced in volume. This mixture is heated at reflux for 1-4 hours, cooled to room temperature to give isocyanate (Vb) which can be reacted with amine (IN) to give product of formula I or precursors thereof.
• Example 1 Synthesis of l-(4-[ " 2-(2-dimethylamino-ethylamino)-6-methyl-pyrimidin-4- yloxy] -naphthalen- 1 -yli -3-(2-methoxy-5-trifluoromethyl-phenyl)-urea
• Boc-aminonaphthol (0.0 g, 0.154 mol) was suspended in 250 mL acetonitrile under nitrogen in a 1000 mL three-neck round bottom flask.
• 1 ,8- Diazabicyclo[5.4.0]undec-7-ene (DBU) (23.5 mL, 0.154 mol) dissolved in a small amount of acetonitrile was added dropwise to the suspension. The solids dissolved to form a clear, green-brownish solution.
• 2-Methoxy-5(trifluoromethyl)aniline (commercially available) (109.7 mg, 0.551 mmol) was dissolved in 14 mL dichloromethane. Saturated aqueous NaHCO 3 solution (14 mL) was added and the mixture was cooled to 0 °C. While stirring, the mixture was treated with phosgene by addition to the organic layer via syringe in one portion (0.95 mL, 1.92 mmol). The mixture was then stirred vigorously for 0.5 h, then the layers were separated. The aqueous layer was extracted once with dichloromethane and the combined organics were dried (MgSO 4 ), filtered and the dichloromethane was removed in vacuo.
• the isocyanate residue was added to the aminonaphthyl pyrimidine ether (186 mg, 0.551 mmol) in 2 mL anhydrous THF.
• the reaction mixture was left stirring at room temperature overnight and then concentrated in vacuo and triturated with ether to provide 250 mg of a pink solid.
• the product was purified by column chromatography on silica gel, eluting with 1:9:90 NH 4 OH:MeOH:CH 2 Cl 2 to provide 110 mg of the title compound as a tan foam.
• nitronaphthalene diazonium tefrafluoroborate salt from above (3.448 g, 12.0 mmol,, 1 equiv.) was suspended in 100 mL xylenes and heated to reflux for 1 h, then allowed to cool back to room temperature. Water was then added and the product extracted twice with ether. The combined extracts were dried (MgSO 4 ), filtered, and the solvents were removed in vacuo.
• the ether intermediate from above (1.244 g, 4.21 mmol) was dissolved in 80 mL EtOH and 20 mL EtOAc.
• Ammonium formate (1.26 g, 20.0 mmol) and palladium-on-carbon catalyst (0.40 g) were added at room temperature, and the mixture was heated to 60 °C for 0.5 - 0.75 h.
• the reaction was allowed to cool back to room temperature and filtered through diatomaceous earth.
• the catalyst was washed with EtOAc, and the filtrates were concentrated in vacuo.
• the residue was purified on silica gel column eluting with EtOAc in hexanes eluent mixtures, providing 555 mg of the desired aminonaphthalene ether intermediate as a light purple foam.
• Example 4 Synthesis of l- 2-methoxy-5-trifluoromethyl-phenylV3-r4-(6-methyl-2- morpholin-4-ylmethyl-pyrimidin-4-yloxy)-naphthalen- 1 -yl]-urea
• the 2-cyano- ⁇ yrimidinyl ether from above (1.95 g, 5.18 mmol) was suspended in 125 mL anhydrous toluene and cooled in an ice bath under an inert atmosphere. After stirring for 0.5 h, a solution of diisobutylaluminum hydride was added dropwise over 40 min. The solution became homogeneous and bright orange/yellow. After stirring at 0 °C for 1 h, the reaction was quenched with sodium-potassium tartrate aqueous solution, stirred vigorously for 15 min then filtered through diatomaceous earth. The precipitate was washed with EtOAc and the organic filtrates were washed with brine and dried (MgSO 4 ). The solution was filtered and concentrated in vacuo. providing 1.08 g of the desired aminomethyl-pyrimidinyl ether as an orange foam, 1.08 g.
• the aminomethyl-pyrimidinyl ether (1.88 g, 4.94 mmol) was suspended in 14.0 mL anhydrous 2-methoxyethyl ether. Potassium carbonate was added (0.81 g, 5.85 mmol), then a catalytic amount of sodium iodide and finally 2-chloroethyl ether (0.58 g, 4.95 mmol). The reaction was heated in a 110 °C bath for 12 h under an inert atmosphere, then allowed to cool. The reaction was then partitioned between water and dichloromethane, the pH adjusted to ⁇ 7 with ammonium chloride aqueous solution. The organics were dried with MgSO 4 , filtered and concentrated in vacuo. .
• the residue (containing some 2-methoxyethyl ether) was purified by column chromatography on silica gel using 0 - 10% MeOH in dichloromethane eluent mixtures to provide 610 mg of desired mo ⁇ holinylmethyl-pyrimidinyl ether (main fraction, 1.35 mmol, 27%) as a brown foam. Also isolated was lower Rf material, which was the de-BOC product ( ⁇ 150 mg).
• 2-Methoxy-5-trifluoromethylaniline (335 mg, 1.75 mmol) was dissolved in 55 mL dichloromethane.
• the mixture was then stirred vigorously for 20 min, then the layers were separated.
• the aqueous layer was extracted once with dichloromethane and the combined organics were dried (Na 2 SO 4 ), filtered and the dichloromethane was removed in vacuo.
• the isocyanate residue in toluene was dissolved in 15 mL anhydrous THF and added to the aminonaphthyl ether from above (569 mg, 1.62 mmol) in 8 mL anhydrous THF, mixed with triethylamine (0.25 mL, 1.79 mmol, 1.1 equiv.). The reaction mixture was left stirring at room temperature overnight, then the reaction was concenfrated in vacuo.
• nitronium tefrafluoroborate (0.146 g, 0.001 mol) at room temperature. After about 6 h, another 0.25 equivs of nitronium tefrafluoroborate was added and the reaction stirred overnight. The reaction was then concentrated in vacuo, and the residue was partitioned between ether and water. The aqueous phase was washed twicw with ether, then the combined organic layers were washed with water, and dried over MgSO 4 . The solvent was removed, resulting in a mobile oil. Kugelrohr distillation of the oil provided 0.2 g of the desired nitrated intermediate which was collected at 100 - 125 °C.
• the 2-methoxy-5-trifluoromethoxyaniline (0.041 g, 0.2 mmol) was dissolved in 5 mL dichloromethane in a 25 mL 3-neck micro round bottom flask and 5 mL of saturated aqueous NaHCO 3 was added. The reaction was cooled to -3 °C in ice-acetone bath. A phosgene/toluene solution was placed in an addition funnel, along with 2 mL dichloromethane and was added dropwise over 10 min. The reaction was stirred another 30 min, then the layers were separated. The aqueous layer was washed twice with dichloromethane, then the combined organics were dried over MgSO 4 , then concentrated to a solution of the isocyanate in toluene.
• the naphthylamine intermediate (0.076 g, mmol) was combined with THF in a 25 mL 3- neck micro flask. The solution was cooled to -5 °C in an ice-acetone bath and the isocyanate solution from above was transferred with THF into an addition funnel and added dropwise over 10 min, and the reaction stirred at room temperature overnight. The solvent was then removed in vacuo and the residue directly run on RP-HPLC to afford the title compound.
• Trifluoroacetic anhydride (30 mL, 0.201 mol) was placed in a 500 mL 3-neck round bottom flask under nitrogen and cooled to -5 °C in ice/acetone bath.
• a 0.5 M solution of 4-methoxyphenyl magnesium bromide in THF 200 mL, 0.100 mol was added dropwise (over an hour), maintaining temperature less than 5 °C.
• the reaction was stirred at room temperature overnight, then heated to reflux for 2 h.
• the THF solvent was removed in vacuo and the residue was partitioned between ether and saturated ammonium chloride aqueous solution.
• reaction mixture was then cooled to room temperature and poured onto hexanes. Upon sitting overnight, crystalline solid formed mixed with a dark gum. The solvent layer was decanted off, and the solid/gum was extracted twice with hexanes. The Combined organics were combined and washed with water. The hexane-soluble material was dried and concentrated in vacuo. The residue was purification by column chromatography on silica gel (10— >35% EtOAc in hexanes), providing both the pentafluoropropene and hexafluoropropane compounds (not fully separable).
• the product was purified by column chromatography on silica gel (10— >35% EtOAc in hexanes eluent). Two fractions were isolated two fractions, a major which came out early, and a late-eluting minor. The title compound (210 mg) was the major, early eluting (less polar).
• the title compound may be coupled to desired naphthylamines in a manner analogous to that described in the above examples.
• Example 7 Synthesis of l- 4-(2-amino-pyrimidin-4-yloxy)-naphthalen-l-yl1-3-(2- methoxy-5-pentafluoroethyl-phenylVurea
• Iodoanisole (2.30 g, 0.010 mol), pentafluoropropionic acid sodium salt (3.70 g, 0.020 mol), and copper iodide (I) (3.80 g, 0.020 mol) were combined in 30 mL toluene and 90 mL DMF in a 250 mL, 3-neck round bottom flask equipped with a Dean Stark trap, condenser, thermometer, and nitrogen inlet.
• the reaction was heated in order to distill off the toluene (removal of water).
• the reaction was stirred a with magnetic stirrer, and the pot temperature raised to almost to 140°C, and the Dean Stark trap was heated with heat gun in order to maintain water removal. About 1.5 mL water was collected. The trap was removed and the reaction brought to reflux for 10 h, and then stirred another 6 h at room temperature.
• the reaction suspension was added to to 200 mL water/200 ml EtOAc and then poured through a pad of diatomaceous earth to remove insolubles.
• the aqueous phase was washed twice with EtOAc.
• the combined EtOAc extracts were washed three times with large portions of water, then dried over MgSO 4 .
• the solution was filtered and concentrated to a yellowish oil, which was subjected to Kugelrohr distillation, maintaining the temperature at or below 60 °C.
• the desired 4-pentafluoroethylanisole was obtained as a clear, mobile liquid.
• the naphthylamine intermediate (0.101 g, 0.40 mmol) was combined with 10 mL THF in 25 mL 3-neck micro round bottom flask and cooled to -5 in °C ice/acetone bath under nitrogen.
• the isocyanate/toluene solution from above in a few mL THF was added dropwise.
• the reaction was stirred on an ice bath for 30 min, then warmed to room temperature and then slowly heated to reflux for about 1 h.
• the reaction was then cooled and concentrated to a thick, red oil.
• the product was purified by column chromatography on silica gel eluting with 5%> to 25% iPrOH in dichloromethane to provide 13 mg of the title compound as an off-white solid, melting point 220-230 (dec).
• Example 8 Synthesis of N-(3- ⁇ 3- 4-(2,6-dimethyl-pyrimidin-4-yloxy -naphthalen-l-yl1- ureido ⁇ -2-methoxy-5 -trifluoromethyl-phenyD-methanesulfonamide
• N-(3-Amino-2-methoxy-5-trifluoromethyl-phenyl)-methanesulfonamide (86 mg, 0.30 mmol) was dissolved in 20 mL dichloromethane. 10 mL Saturated aqueous NaHCO 3 solution was added, the mixture was cooled to 0 °C and, while not stirring, the mixture was treated with phosgene (0.6 mL of a 2 M solution in toluene, 1.2 mmol) by addition to the organic layer via syringe in one portion. The mixture was then stirred vigorously for 25 min, then the layers were separated.
• Pharmacokinetic properties of p38 inhibitor compounds can be measured by known methods. Inhibition of p38 MAP kinase and inhibition of cytokine production are measured as follows: Inhibition of P38 MAP Kinase
• a fluorescence binding assay is used as described [Pargellis,C, Tong,L., Churchill,L., Cirillo,P.F., Gilmore,T., Graham,A.G., Grob,P.M., Hickey,E.R., Moss,N., Pav,S. & Regan,J. Inhibition of p38 MAP kinase by utilizing a novel allosteric binding site. Nature Structural Biology 9, 268-272 (2002)].
• Binding studies are conducted in aqueous solutions prepared using binding buffer: 20 mM Bis-TRIS Propane (pH 7.0), 2 mM EDTA, 0.01 % NaN 3 , and 0.15 % n-octylglucoside.
• Kinetic data for the association of SK&F 86002 to p38 MAP kinase is collected on a Kintech fluorescence detector system equipped with a stopped flow controller. The data is fit simultaneously to an appropriate equation describing kinetic binding for a simple 1-step binding mechanism [Morelock,M.M., Pargellis,C.A., Graham,E.T., Lamarre,D. & Jung,G.
• Time-resolved ligand exchange reactions kinetic models for competitive inhibitors with recombinant human renin. J. Med. Chem. 38, 1751-1761 (1995)].
• the exchange curve assays are run as two half reactions using an SLM Aminco Bowman Series 2 Model SQ-340 fluorescence detector. Preliminary equilibrium are set up with two half reactions differing in the order of addition of the two p38 MAP kinase inhibitors, hi the first half reaction, p38 MAP kinase and SK&F 86002 are preincubated for 3 minutes. In the second half reaction p38 MAP kinase is preincubated with BIRB 796 for 60 minutes.
• a net dissociation of the fluorescent probe, SK&F 86002 is observed for the first half reaction and a net association is observed for the second half reaction.
• the raw data from both half reactions are fitted simultaneously to an equation describing simple competitive inhibition[Morelock,M.M., Pargellis,C.A., Graham,E.T., Lamarre,D. & Jung,G. Time- resolved ligand exchange reactions: kinetic models for competitive inhibitors with recombinant human renin. J. Med. Chem. 38, 1751-1761 (1995)].
• BIRB 796 (chemical name: l-(5-tert-butyl-2- -tolyl-2H-pyrazol-3-yl)-3-[4-(2-mo ⁇ holin-4-yl-ethoxy)- naphthalen-l-yl]-urea) was synthesized as described [Cirillo,P., Gilmore,T.A., ⁇ ickey,E., Regan,J. & Zhang,L.H. Aromatic heterocyclic compounds as antiinflammatory agents.
• Preferred compounds were evaluated and had IC 50 ⁇ 1 ⁇ M in this assay, confirming inhibition of p38 MAP Kinase.
• the compounds of the invention possess selectivity for p38 MAP Kinase over one or more kinases.
• kinases include Src family of kinases, especially Lyn.
• the inhibition of cytokine production can be observed by measuring inhibition of TNF ⁇ in lipopolysaccharide stimulated THP cells (for example, see W. Prichett et al, 1995, J. Inflammation, 45, 97). All cells and reagents were diluted in RPMI 1640 with phenol red and L-glutamine, supplemented with additional L-glutamine (total: 4 mM), penicillin and streptomycin (50 units/ml each) and fetal bovine serum (FBS, 3%) (GLBCO, all cone. final). Assay was performed under sterile conditions; only test compound preparation was nonsterile.
• LPS lipopolysaccharide
• Assay was terminated by centrifuging plates 5 min, room temperature, 1600 rpm (400 x g); supernatants were transferred to clean 96 well plates and stored - 80°C until analyzed for human TNF ⁇ by a commercially available ELISA kit (Biosource #KHC3015, Camarillo, CA). Data was analyzed by non-linear regression (Hill equation) to generate a dose response curve using SAS Software System (SAS institute, Inc., Gary, NC). The calculated IC 5 o value is the concentration of the test compound that caused a 50% decrease in the maximal TNF ⁇ production.
• Preferred compounds have an IC 50 ⁇ 1 uM in this assay.
• peripheral blood monocytic cells By similar methods using peripheral blood monocytic cells, appropriate stimuli, and commercially available ELISA kits (or other method of detection such as radioimmunoassay), for a particular cytokine, inhibition of IL-lbeta, GM-CSF, IL-6 and IL-8 can be demonstrated for preferred compounds (for example, see J.C. Lee et al, 1988, int. J. Immunopharmacol, 10, 835).

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• 2003
  • 2003-08-01 CA CA002494824A patent/CA2494824A1/en not_active Abandoned
  • 2003-08-01 US US10/632,998 patent/US6872726B2/en not_active Expired - Lifetime
  • 2003-08-01 WO PCT/US2003/024095 patent/WO2004014870A1/en not_active Ceased
  • 2003-08-01 EP EP03784873A patent/EP1549621A1/en not_active Withdrawn
  • 2003-08-01 AU AU2003257991A patent/AU2003257991A1/en not_active Abandoned
  • 2003-08-01 JP JP2004527704A patent/JP2006504667A/ja active Pending
  • 2003-08-04 UY UY27924A patent/UY27924A1/es not_active Application Discontinuation
  • 2003-08-04 PE PE2003000769A patent/PE20040755A1/es not_active Application Discontinuation
  • 2003-08-07 TW TW092121657A patent/TW200407113A/zh unknown
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• 2004
  • 2004-09-14 US US10/940,898 patent/US7279475B2/en not_active Expired - Lifetime

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