Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2002-04-02
2003-09-09
Solola, T. A. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S253010, C514S254050, C514S319000, C514S341000, C544S124000, C544S364000, C546S206000, C546S256000, C546S275400
Reexamination Certificate
active
06617324
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to a novel group of pyrazole compounds, compositions and methods for treating p38 kinase mediated disorders.
BACKGROUND OF THE INVENTION
Mitogen-activated protein kinases (MAP) is a family of proline-directed serine/threonine kinases that activate their substrates by dual phosphorylation. The kinases are activated by a variety of signals including nutritional and osmotic stress, UV light, growth factors, endotoxin and inflammatory cytokines. The p38 MAP kinase group is a MAP family of various isoforms, including p38&agr;, p38&bgr; and p38&ggr;, and is responsible for phosphorylating and activating transcription factors (e.g. ATF2, CHOP and MEF2C) as well as other kinases (e.g. MAPKAP-2 and MAPKAP-3). The p38 isoforms are activated by bacterial lipopolysaccharide, physical and chemical stress and by pro-inflammatory cytokines, including tumor necrosis factor (TNF-&agr;) and interleukin-1 (IL-1). The products of the p38 phosphorylation mediate the production of inflammatory cytokines, including TNF and IL-1, and cyclooxygenase-2.
TNF-&agr; is a cytokine produced primarily by activated monocytes and macrophages. Excessive or unregulated TNF production has been implicated in mediating a number of diseases. Recent studies indicate that TNF has a causative role in the pathogenesis of rheumatoid arthritis. Additional studies demonstrate that inhibition of TNF has broad application in the treatment of inflammation, inflammatory bowel disease, multiple sclerosis and asthma.
TNF has also been implicated in viral infections, such as HIV, influenza virus, and herpes virus including herpes simplex virus type-1 (HSV-1), herpes simplex virus type-2 (HSV-2), cytomegalovirus (CMV), varicella-zoster virus (VZV), Epstein-Barr virus, human herpesvirus-6 (HHV-6), human herpesvirus-7 (HHV-7), human herpesvirus-8 (HHV-8), pseudorabies and rhinotracheitia, among others.
IL-8 is another pro-inflammatory cytokine, which is produced by mononuclear cells, fibroblasts, endothelial cells, and keratinocytes, and is associated with conditions including inflammation.
IL-1 is produced by activated monocytes and macrophages and is involved in the inflammatory response. IL-1 plays a role in many pathophysiological responses including rheumatoid arthritis, fever and reduction of bone resorption.
TNF, IL-1 and IL-8 affect a wide variety of cells and tissues and are important inflammatory mediators of a wide variety of disease states and conditions. The inhibition of these cytokines by inhibition of the p38 kinase is of benefit in controlling, reducing and alleviating many of these disease states.
Various pyrazoles have previously been described. U.S. Pat. No. 4,000,281, to Beiler and Binon, describes 4,5-aryl/heteroaryl substituted pyrazoles with antiviral activity against both RNA and DNA viruses such as myxoviruses, adenoviruses, rhinoviruses, and various viruses of the herpes group. WO 92/19615, published Nov. 12, 1992, describes pyrazoles as novel fungicides. U.S. Pat. No. 3,984,431, to Cueremy and Renault, describes derivatives of pyrazole-5-acetic acid as having anti-inflammatory activity. Specifically, [1-isobutyl-3,4-diphenyl-1H-pyrazol-5-yl]acetic acid is described. U.S. Pat. No. 3,245,093 to Hinsgen et al, describes a process for preparing pyrazoles. WO 83/00330, published Feb. 3, 1983, describes a new process for the preparation of diphenyl-3,4-methyl-5-pyrazole derivatives. WO 95/06036, published Mar. 2, 1995, describes a process for preparing pyrazole derivatives. U.S. Pat. No. 5,589,439, to T. Goto, et al., describes tetrazole derivatives and their use as herbicides. EP 515,041 describes pyrimidyl substituted pyrazole derivatives as novel agricultural fungicides. Japanese Patent 4,145,081 describes pyrazolecarboxylic acid derivatives as herbicides. Japanese Patent 5,345,772 describes novel pyrazole derivatives as inhibiting acetylcholinesterase.
Pyrazoles have been described for use in the treatment of inflammation. Japanese Patent 5,017,470 describes synthesis of pyrazole derivatives as anti-inflammatory, anti-rheumatic, anti-bacterial and anti-viral drugs. EP 115640, published Dec. 30, 1983, describes 4-imidazolyl-pyrazole derivatives as inhibitors of thromboxane synthesis. 3-(4-Isopropyl-1-methylcyclohex-1-yl)-4-(imidazol-1-yl)-1H-pyrazole is specifically described. WO 97/01551, published Jan. 16, 1997, describes pyrazole compounds as adenosine antagonists. 4-(3-Oxo-2,3-dihydropyridazin-6-yl)-3-phenylpyrazole is specifically described. U.S. Pat. No. 5,134,142, to Matsuo et al. describes 1,5-diaryl pyrazoles as having anti-inflammatory activity.
U.S. Pat. No. 5,559,137 to Adams et al, describes novel pyrazoles (1,3,4,-substituted) as inhibitors of cytokines used in the treatment of cytokine diseases. Specifically, 3-(4-fluorophenyl)-1-(4-methylsulfinylphenyl)-4-(4-pyridyl)-5H-pyrazole is described. WO 96/03385, published Feb. 8, 1996, describes 3,4-substituted pyrazoles, as having anti-inflammatory activity. Specifically, 3-methylsulfonylphenyl-4-aryl-pyrazoles and 3-aminosulfonylphenyl-4-aryl-pyrazoles are described.
Laszlo et al.,
Bioorg. Med. Chem. Letters
, 8 (1998) 2689-2694, describes certain furans, pyrroles and pyrazolones, particularly 3-pyridyl-2,5-diaryl-pyrroles, as inhibitors of p38 kinase.
The invention's pyrazolyl compounds are found to show usefulness as p38 kinase inhibitors.
REFERENCES:
patent: 3254093 (1966-05-01), Huisgen et al.
patent: 3984431 (1976-10-01), Gueremy et al.
patent: 4000281 (1976-12-01), Beiler et al.
patent: 5051518 (1991-09-01), Murray et al.
patent: 5134142 (1992-07-01), Matsuo et al.
patent: 5486534 (1996-01-01), Lee et al.
patent: 5559137 (1996-09-01), Adams et al.
patent: 5589439 (1996-12-01), Goto et al.
patent: 5658903 (1997-08-01), Adams et al.
patent: 5739143 (1998-04-01), Adams et al.
patent: 5756529 (1998-05-01), Isakson et al.
patent: 5972972 (1999-10-01), Mihelich et al.
patent: 5998425 (1999-12-01), Adams et al.
patent: 6423713 (2002-07-01), Anantanarayan et al.
patent: 295 374 (1991-10-01), None
patent: 0 115 640 (1983-12-01), None
patent: 0 515 041 (1992-11-01), None
patent: 0 531 901 (1993-03-01), None
patent: 0 418 845 (1995-08-01), None
patent: 0 846 686 (1998-06-01), None
patent: 0 846 687 (1998-06-01), None
patent: 4-145081 (1992-05-01), None
patent: 5-17470 (1993-01-01), None
patent: 5-345772 (1993-12-01), None
patent: 8-183787 (1996-07-01), None
patent: WO 83/00330 (1983-02-01), None
patent: WO 92/19615 (1992-11-01), None
patent: WO 94/19350 (1994-09-01), None
patent: WO 95/06036 (1995-03-01), None
patent: WO 95/22545 (1995-08-01), None
patent: WO 95/31451 (1995-11-01), None
patent: WO 96/03385 (1996-02-01), None
patent: WO 96/21452 (1996-07-01), None
patent: WO 96/21654 (1996-07-01), None
patent: WO 96/40143 (1996-12-01), None
patent: WO 97/01551 (1997-01-01), None
patent: WO 97/23479 (1997-07-01), None
patent: WO 97/25046 (1997-07-01), None
patent: WO 97/25047 (1997-07-01), None
patent: WO 97/25048 (1997-07-01), None
patent: WO 97/32583 (1997-09-01), None
patent: WO 97/35855 (1997-10-01), None
patent: WO 97/35856 (1997-10-01), None
patent: WO 97/47618 (1997-12-01), None
patent: WO 98/07425 (1998-02-01), None
patent: WO 98/16230 (1998-04-01), None
patent: WO 98/25619 (1998-06-01), None
patent: WO 98/52940 (1998-11-01), None
patent: WO 98/52941 (1998-11-01), None
patent: WO 98/52937 A2 (1998-11-01), None
patent: WO 98/57966 (1998-12-01), None
patent: WO 99/01130 (1999-01-01), None
patent: WO 99/01131 (1999-01-01), None
patent: WO 99/01136 (1999-01-01), None
patent: WO 99/01452 (1999-01-01), None
patent: WO 99/17776 (1999-04-01), None
patent: WO 99/32121 (1999-07-01), None
patent: WO 99/61426 (1999-12-01), None
U.S. patent application Ser. No. 09/196,623, Anantanaryan et al., filed Nov. 20, 1998.
U.S. patent application Ser. No. 09/513,351, Anantanarayan et al., filed Feb. 20, 2000.
Adams, J.L., et al., “Pyrimidinylimidazole Inhibitors of CSBP/p38 Kinase Demonstrating Decreased Inhibition of Hepatic Cytochrome p450 Enzymes”,Bioorganic&Medicinal Chemistry Letters, vol. 8, pp. 31
Clare Michael
Collins Paul W.
Crich Joyce Zuowu
Devraj Rajesh
Flynn Daniel L.
G. D. Searle & Company
Gryte David M.
Harness & Dickey & Pierce P.L.C.
Solola T. A.
LandOfFree
Substituted pyrazoles as p38 kinase inhibitors does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Substituted pyrazoles as p38 kinase inhibitors, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Substituted pyrazoles as p38 kinase inhibitors will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3040605