Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-02-12
2003-01-21
Aulakh, C. S. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S275400, C546S256000, C544S360000, C514S252010, C514S333000
Reexamination Certificate
active
06509361
ABSTRACT:
TECHNICAL FIELD
This invention is directed to kinases inhibitors, and more particularly to 1,5-diaryl substituted pyrazole compounds that, inter alia, inhibit the activity of mitogen-activated protein kinases, compositions of those inhibitors, intermediates for the syntheses of those compounds, and processes for treating pathological mitogen-activated protein kinase activity.
BACKGROUND OF THE INVENTION
Mitogen-activated protein (MAP) kinases are 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, p38 and p38, 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 alpha (TNF-) and interleukin-1 (IL-1). The products of the p38 phosphorylation mediatethe production of inflammatory cytokines, including TNF and IL-1, and cyclooxygenase-2.
TNF-a 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 rhinotracheitis, 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 also 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. For example, WO 95/33727, published Dec. 14, 1995, describes substituted pyrazoles as corticotropin-releasing factor (CFR) antagonists used in the treatment of illnesses such as stress and anxiety related disorders. WO 96/21660, published Jul. 18, 1996, describes substituted pyrazoles and their use as ligands for dopamine receptors within the body. EP 0 699 438 A2, published Mar. 6, 1996, describes pyrazoles and their use as neurotensin antagonists. U.S. Pat. No. 2,833,779, to Fields et al., describes the preparation of 1,3,5-tri-substituted pyrazoles. U.S. Pat. No. 4,957,971, to Picard et al., describes trans-6-[2-(N-heteroaryl-3,5-disubstituted)pyrazol-4-yl)ethyl- or ethenyl]tetrahydro-4-hydroxy-2H-pyran-2-ones as potent inhibitors of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase, used for inhibiting cholesterol biosynthesis. U.S. Pat. No. 5,441,975, to Lee et al., describes pyrazoles that are useful for the treatment of hypercholesterolemia or atherosclerosis in mammals. WO 93/04052, published Mar. 4, 1993, describes pyrazole having ACAT inhibitory activity. U.S. Pat. No. 5,102,893, to Picard et al., describes trans-6-[2-(N-heteroaryl-3,5-disubstituted)pyrazol-4-yl)ethyl- or ethenyl]tetrahydro-4-hydroxy-2H-pyran-2-ones which are potent inhibitors of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase and useful as hydrolipidemic and hypocholesterolemic agents. WO 94/22838, published Oct. 13, 1994, describes pyrazole compounds having angiotensin II antagonism which are useful in preventing or treating hypertension, congestive heart failure, chronic renal failure, aldosteronism, and increased intralocular pressure.
WO 92/19615, published Nov. 12, 1992, describes pyrazoles, pyrazolines and tetrahydropyridazine having fungicidal activity. U.S. Pat. No. 5,232,940, to Hatton et al., describes a N-Phenylpyrazole and their use against arthropod, plant nematode, helminth and protozoan pests. WO 95/01340, published Jan. 12, 1995, describes novel pyrazole compounds having agrohorticultural bactericidal effect. U.S. Pat. No. 5,201,938, to Costales, describes novel substituted N-pyrazolyl-1,2,4-triazolo[1,5-c]-pyrimidine-2-sulfonamide compounds and their use as herbicides. WO 93/09100, published May 13, 1993, describes trizolocarboxamides with herbicidal activity used to control blackgrass, wild oats, crabgrass, giant foxtail, and barnyardgrass. WO 94/29300, published Dec. 22, 1994, describes pyrazoles 3-substituted by a heterocyclic ring and their use as agricultural fungicides. WO 96/37477, published Nov. 28, 1996, describes substituted pyrazoles and their use against animal parasites and pests and as insecticides, and fungicides.
Pyrazoles have also been described for use in the treatment of inflammation. U.S. Pat. No. 5,242,940, to Wachter and Murray, describes 1,5 heterocyclic pyrazoles and their use in alleviating inflammatory and cardiovascular disorders in mammals. U.S. Pat. No. 5,134,142, to Matsuo, et al., describes 1,5 diaryl substituted pyrazoles and 1,3 diaryl substituted pyrazoles useful in the treatment of inflammation, pain, thrombosis and rheumatism. U.S. Pat. No. 5,466,823, to Talley et al., describes a class of pyrazole benzenesulfonamide compounds and their use in treating inflammation and inflammation-related disorders.
The invention's pyrazolyl compounds are found to show usefulness, inter alia, as p38 kinase inhibitors.
BRIEF SUMMARY OF THE INVENTION
In accordance with the present invention, it has been found that certain 1,5-diaryl pyrazoles are effective for inhibition of mitogen-activated protein (MAP) kinases. Mitogen-activated protein kinases are believed to be associated with, inter alia, the mediation of a number of inflammatory diseases. In particular, it has been found that these certain 1,5-diaryl pyrazoles are effective for the inhibition of the p38 MAP kinase group, a sub-family of MAP kinases. The compounds of interest here have structures that correspond to Formula I, below, whose substituent groups are defined hereinafter, or a pharmaceutically acceptable salt thereof.
A process for treating a host mammal having a condition associated with pathological p38 MAP kinase activity is also contemplated. That process comprises administering a compound described herein in a p38 MAP kinase enzyme-inhibiting effective amount to a mammalian host having such a condition. The use of administration repeated a plurality of times is particularly contemplated.
The p38 MAP kinase sub-family have various isoforms, including p38, p38 and p38 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-) 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.
Excessive or unregulated TNF production has been implicated in mediating a number of diseases, including rheumatoid arthritis, inflammatio
Collins Paul W.
Crich Joyce Z.
Weier Richard M.
Xu Xiang Dong
Aulakh C. S.
Gryte, Esq. David M.
Harness & Dickey & Pierce P.L.C.
Pharmacia Corporation
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