Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1998-05-22
2002-02-05
Criares, Theodore J. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S439000, C514S461000, C514S588000, C514S596000
Reexamination Certificate
active
06344476
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to the use of a group of aryl ureas in treating cytokine mediated diseases and proteolytic enzyme mediated diseases, and pharmaceutical compositions for use in such therapy.
BACKGROUND OF THE INVENTION
Two classes of effector molecules which are critical for the progression of rheumatoid arthritis are pro-inflammatory cytokines and tissue degrading proteases. Recently, a family of kinases was described which is instrumental in controlling the transcription and translation of the structural genes coding for these effector molecules.
The MAP kinase family is made up of a series of structurally related proline-directed serine/threonine kinases which are activated either by growth factors (such as EGF) and phorbol esters (ERK), or by IL-1, TNF&agr; or stress (p38, JNK). The MAP kinases are responsible for the activation of a wide variety of transcription factors and proteins involved in transcriptional control of cytokine production. A pair of novel protein kinases involved in the regulation of cytokine synthesis was recently described by a group from SmithKline Beecham (Lee et al.
Nature
1994, 372, 739). These enzymes were isolated based on their affinity to bond to a class of compounds, named CSAIDs cytokine suppressive anti-inflammatory drugs) by SKB. The CSAIDs, pyridinyl imidazoles, have been shown to have cytokine inhibitory activity both in vitro and in vivo. The isolated enzymes, CSBP-1 and -2 (CSAID binding protein 1 and 2) have been cloned and expressed. A murine homologue for CSBP-2, p38, has also been reported (Han et al.
Science
1994, 265, 808).
Early studies suggested that CSAIDs function by interfering with m-RNA translational events during cytokine biosynthesis. Inhibition of p38 has been shown to inhibit both cytokine production (eg., TNF&agr;, IL-1, IL-6, IL-8; Lee et al.
N.Y. Acad. Sci.
1993, 696, 149) and proteolytic enzyme production (eg., MMP-1, MMP-3; Ridley et al.
J. Immunol.
1997, 158, 3165) in vitro and/or in vivo.
Clinical studies have linked TNF&agr; production and/or signaling to a number of diseases including rheumatoid arthritis (Maini.
J. Royal Coll. Physicians London
1996, 30, 344). In addition, excessive levels of TNF&agr; have been implicated in a wide variety of inflammatory and/or immunomodulatory diseases, including acute rheumatic fever (Yegin et al.
Lancet
1997, 349, 170), bone resorption (Pacifici et al.
J. Clin. Endocrinol. Metabol.
1997, 82, 29), postmenopausal osteoporosis (Pacifici et al.
J. Bone Mineral Res.
1996, 11, 1043), sepsis (Blackwell et al.
Br. J. Anaesth.
1996, 77, 110), gram negative sepsis (Debets et al.
Prog. Clin. Biol. Res.
1989, 308, 463), septic shock (Tracey et al.
Nature
1987, 330, 662; Girardin et al.
New England J. Med.
1988, 319, 397), endotoxic shock (Beutler et al.
Science
1985, 229, 869; Ashkenasi et al.
Proc. Nat'l. Acad. Sci. USA
1991, 88, 10535), toxic shock syndrome (Saha et al.
J. Immunol.
1996, 157, 3869; Lina et al.
FEMS Immunol. Med. Microbiol.
1996, 13, 81), systemic inflammatory response syndrome (Anon.
Crit. Care Med.
1992, 20, 864), inflammatory bowel diseases (Stokkers et al.
J. Inflamm.
1995-6, 47, 97) including Crohn's disease (van Deventer et al.
Aliment. Pharmacol. Therapeu.
1996, 10 (Suppl. 2), 107; van Dullemen et al.
Gastroenterology
1995, 109, 129) and ulcerative colitis (Masuda et al.
J. Clin. Lab. Immmunol.
1995, 46, 111), Jarisch-Herxheimer reactions (Fekade et al.
New England J. Med.
1996, 335, 311), asthma (Amrani et al.
Rev. Malad. Respir.
1996, 13, 539), adult respiratory distress syndrome (Roten et al.
Am. Rev. Respir. Dis.
1991, 143, 590; Suter et al.
Am. Rev. Respir. Dis.
1992, 145, 1016), acute pulmonary fibrotic diseases (Pan et al.
Pathol. Int.
1996, 46, 91), pulmonary sarcoidosis (Ishioka et al.
Sarcoidosis Vasculitis Diffuse Lung Dis.
1996, 13, 139), allergic respiratory diseases (Casale et al.
Am. J. Respir. Cell Mol. Biol.
1996, 15, 35), silicosis (Gossart et al.
J. Immunol.
1996, 156, 1540; Vanhee et al.
Eur. Respir. J.
1995, 8, 834), coal worker's pneumoconiosis (Borm et al.
Am. Rev. Respir. Dis.
1988, 138, 1589), alveolar injury (Horinouchi et al.
Am. J. Respir. Cell Mol. Biol.
1996, 14, 1044), hepatic failure (Gantner et al.
J. Pharmacol. Exp. Therap.
1997, 280, 53), liver disease during acute inflammation (Kim et al.
J. Biol. Chem.
1997, 272, 1402), severe alcoholic hepatitis (Bird et al.
Ann. Intern. Med.
1990, 112, 917), malaria (Grau et al.
Immunol. Rev.
1989, 112, 49; Taverne et al.
Parasitol. Today
1996, 12, 290) including Plasmodium falciparum malaria (Perlmann et al.
Infect. Immunit.
1997, 65, 116) and cerebral malaria (Rudin et al.
Am. J. Pathol.
1997, 150, 257), non-insulin-dependent diabetes mellitus (NIDDM; Stephens et al.
J. Biol. Chem.
1997, 272, 971; Ofei et al.
Diabetes
1996, 45, 881), congestive heart failure (Doyama et al.
Int. J. Cardiol.
1996, 54, 217; McMurray et al.
Br. Heart J.
1991, 66, 356), damage following heart disease (Malkiel et al.
Mol. Med. Today
1996, 2, 336), atherosclerosis (Parums et al.
J. Pathol.
1996, 179, A46), Alzheimer's disease (Fagarasan et al.
Brain Res.
1996, 723, 231; Aisen et al.
Gerontology
1997, 43, 143), acute encephalitis (Ichiyama et al.
J. Neurol.
1996, 243, 457), brain injury (Cannon et al.
Crit. Care Med.
1992, 20, 1414; Hansbrough et al.
Surg. Clin. N. Am.
1987, 67, 69; Marano et al.
Surg. Gynecol. Obstetr.
1990, 170, 32), multiple sclerosis (M. S.; Coyle.
Adv. Neuroimmunol.
1996, 6, 143; Matusevicius et al.
J. Neuroimmunol.
1996, 66, 115) including demyelation and oligiodendrocyte loss in multiple sclerosis (Brosnan et al.
Brain Pathol.
1996, 6, 243), advanced cancer (MucWierzgon et al.
J. Biol. Regulators Homeostatic Agents
1996, 10, 25), lymphoid malignancies (Levy et al.
Crit. Rev. Immunol.
1996, 16, 31), pancreatitis (Exley et al.
Gut
1992, 33, 1126) including systemic complications in acute pancreatitis (McKay et al.
Br. J. Surg.
1996, 83, 919), impaired wound healing in infection inflammation and cancer (Buck et al.
Am. J. Pathol.
1996, 149, 195), myelodysplastic syndromes (Raza et al.
Int. J. Hematol.
1996, 63, 265), systemic lupus erythematosus (Maury et al.
Arthritis Rheum.
1989, 32, 146), biliary cirrhosis (Miller et al.
Am. J. Gasteroenterolog.
1992, 87, 465), bowel necrosis (Sun et al.
J. Clin. Invest.
1988, 81, 1328), psoriasis (Christophers.
Austr. J. Dermatol.
1996, 37, S4), radiation injury (Redlich et al.
J. Immunol.
1996, 157, 1705), and toxicity following administration of monoclonal antibodies such as OKT3 (Brod et al.
Neurology
1996, 46, 1633). THF&agr; levels have also been related to host-versus-graft reactions (Piguet et al.
Immunol. Ser.
1992, 56, 409) including ischemia reperfusion injury (Colletti et al.
J. Clin. Invest.
1989, 85, 1333) and allograft rejections including those of the kidney (Maury et al.
J. Exp. Med.
1987, 166, 1132), liver (Imagawa et al.
Transplantation
1990, 50, 219), heart (Bolling et al.
Transplantation
1992, 53, 283), and skin (Stevens et al.
Transplant. Proc.
1990, 22, 1924), lung allograft rejection (Grossman et al.
Immunol. Allergy Clin. N. Am.
1989, 9, 153) including chronic lung allograft rejection (obliterative bronchitis; LoCicero et al.
J. Thorac. Cardiovasc. Surg.
1990, 99, 1059), as well as complications due to total hip replacement (Cirino et al.
Life Sci.
1996, 59, 86). THF&agr; has also been linked to infectious diseases (review: Beutler et al.
Crit. Care Med.
1993, 21, 5423; Degre.
Biotherapy
1996, 8, 219) including tuberculosis (Rook et al.
Med. Malad. Infect.
1996, 26, 904),
Helicobacter pylori
infection during peptic ulcer disease (Beales et al.
Gastroenterology
1997, 112, 136), Chaga's disease resulting from
Trypanosoma cruzi
infection (Chandrasekar et al.
Biochem. Biophys. Res. Commun.
1996, 223, 365), effects of Shiga-like toxin resulting from
E. coli
infection (Harel et al.
J. Clin. Invest.
1992, 56, 40), th
Bombara Michael
Chen Jinshan
Gunn David
Paulsen Holger
Ranges Gerald
Bayer Corporation
Criares Theodore J.
Millen White Zelano & Branigan P.C.
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