Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-10-31
2002-09-24
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S242000, C514S247000, C514S252100, C514S255050, C514S256000, C514S277000, C514S403000, C514S406000, C514S407000, C544S180000, C544S182000, C544S224000, C544S238000, C544S242000, C544S336000, C546S001000, C548S356100, C548S366100, C548S364100, C548S364700, C548S367100, C548S379100, C549S049000, C549S074000, C549S200000, C549S229000
Reexamination Certificate
active
06455525
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates generally to heterocyclic substituted pyrazolones, including pharmaceutical compositions, diagnostic kits, assay standards or reagents containing the same, and methods of using the same as therapeutics. The invention is also directed to intermediates and processes for making these novel compounds.
BACKGROUND OF THE INVENTION
Protein kinases play a critical role in the control of cell growth and differentiation. Aberrant expression or mutations in protein kinases have been shown to lead to uncontrolled cell proliferation, such as malignant tumor growth, and various defects in developmental processes, including cell migration and invasion, and angiogenesis. Protein kinases are therefore critical to the control, regulation, and modulation of cell proliferation in diseases and disorders associated with abnormal cell proliferation. Protein kinases have also been implicated as targets in central nervous system disorders such as Alzheimer's disease, inflammatory disorders such as psoriasis, bone diseases such as osteoporosis, atheroscleroses, restenosis, thrombosis, metabolic disorders such as diabetes, and infectious diseases such as viral and fungal infections.
One of the most commonly studied pathways involving kinase regulation is cellular signaling from receptors at the cell surface to the nucleus. Generally, the function of each receptor is determined by its pattern of expression, ligand availability, and the array of downstream signal transduction pathways that are activated by a particular receptor. One example of this pathway includes a cascade of kinases in which members of the Growth Factor receptor Tyrosine Kinases deliver signals via phosphorylation to other kinases such as Src Tyrosine kinase, and the Raf, Mek and Erk serine/threonine kinase families. Each of these kinases is represented by several family members which play related, but functionally distinct roles. The loss of regulation of the growth factor signaling pathway is a frequent occurrence in cancer as well as other disease states. Fearon,
Genetic Lesions in Human Cancer, Molecular Oncology,
1996, 143-178.
The raf1 serine/threonine kinase can be activated by the known oncogene product ras. The raf kinase enzyme positively regulates cell division through the Raf/MEK/ERK protein kinase cascade. This activation is the result of cRaf1 catalyzed phosphorylation of the protein kinase, MEK1, which phosphorylates and activates the protein kinase ERK. ERK phosphorylates and regulates transcription factors required for cell division. Avruch et al.,
TIBS,
1994 (19) 279-283. cRaf1 negatively regulates cell death by modulation of the activity of Bcl-2, a critical regulator of apoptosis. This regulation involves direct phosphorylation of Bcl-2 family members. Gajewski and Thompson,
Cell,
1996 (87) 619-628.
These aspects of cRaf1-mediated regulation of cell proliferation require the kinase activity of cRaf1. It has also been reported that the reduction of Raf protein levels correlates with a reduction in tumor growth rate in vivo tumor mouse models. Monia, Johnston, Geiger, Muller, and Fubro,
Nature Medicine
, Vol. 2, No. 6, June 1996, 668-674. Inhibitors of the kinase activity of cRaf1 should therefore provide effective treatment for a wide variety of human cancers.
Activation of the MAP kinase signaling pathways represents an attractive target for tumor therapy by inhibiting one or more of the kinases involved. An additional member of the MAP kinase family of proteins is the p38 kinase, alternatively known as the cytokine suppressive drug binding protein or reactivation kinase, RK. Activation of this kinase has been implicated in the production of proinflammatory cytokines such as IL-1 and TNF. Inhibition of this kinase could therefore offer a treatment for disease states in which disregulated cytokine production is involved.
The signals mediated by kinases have also been shown to control cell growth, cell death and differentiation in the cell by regulating the processes of the cell cycle. Progression through the eukaryotic cell cycle is controlled by a family of kinases called cyclin dependent kinases (CDKs). The loss of control of CDK regulation is a frequent event in hyperproliferative diseases and cancer.
Inhibitors of kinases involved in mediating or maintaining particular disease states represent novel therapies for these disorders. Examples of such kinases include inhibition of Src, raf, and the cyclin-dependent kinases (CDK) 1, 2, and 4 in cancer, CDK2 or PDGF-R kinase in restenosis, CDK5 and GSK3 kinases in Alzheimers, c-Src kinase in osteoporosis, GSK-3 kinase in type-2 diabetes, p38 kinase in inflammation, VEGF-R 1-3 and TIE-1 and -2 kinases in angiogenesis, UL97 kinase in viral infections, CSF-1R kinase in bone and hematopoetic diseases, and Lck kinase in autoimmune diseases and transplant rejection.
Thus, there is a need for novel classes of compounds which demonstrate activity toward receptor and non-receptor types of protein kinases. It has been discovered that a class of compounds, referred to herein as heterocyclic-substituted pyrazolones, are useful as agents for the regulation of protein kinase. The present invention is therefore directed to, inter alia, their use as therapetic agents for the treatment of the foregoing disorders.
SUMMARY OF THE INVENTION
Accordingly, one object of the present invention is to provide novel compounds which are kinase inhibitors. In certain objects, the compounds of the present invention are inhibitors of one or more of vascular endothelial growth factor receptor (VEGFR) kinase, trkA tyrosine kinase (trkA), mixed lineage kinase (MLK) or fibroplast growth factor receptor kinase (FGFR).
It is another object of the present invention to provide pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention, or a pharmaceutically acceptable salt form thereof.
It is another object of the present invention to provide a novel method for treating or preventing disorders associated with the aberrant activity of protein kinases. In certain objects, the disorders are characterized by the aberrant activity of one or more of the vascular endothelial growth factor receptor (VEGFR) kinase, trkA tyrosine kinase (trkA), mixed lineage kinase (MLK) or fibroplast growth factor receptor kinase (FGFR), and the method comprises administering to a host in need of such treatment or prevention a therapeutically effective amount of at least one of the compounds of the present invention.
It is another object of the present invention to provide a method for inhibiting protein kinases in a body fluid sample. In certain objects, the method comprises treating the body fluid sample with an effective amount of at least one of the compounds of the present invention to inhibit one or more protein kinases.
It is another object of the present invention to provide a kit or container containing at least one of the compounds of the present invention in an amount effective for use as a diagnostic, standard or reagent.
These and other important objects, which will become apparent during the following detailed description, have been achieved by the inventor's discovery that compounds of Formula I:
stereoisomeric forms, mixtures of stereoisomeric forms, or pharmaceutically acceptable salt forms thereof, wherein R
1
, R
2
, R
3
, R
4
, R
5
, and Het are defined below, are effective kinase inhibitors.
DETAILED DESCRIPTION OF THE EMBODIMENTS
Thus, in a first embodiment, the present invention provides a novel compound of Formula I:
or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:
Het is a heterocycle;
R
1
is selected from H, C
1-10
alkyl substituted with 0-5 R
6
, C
2-8
alkenyl substituted with 0-5 R
6
, C
2-8
alkynyl substituted with 0-5 R
6
, NR
a
R
a
, C(═O)R
b
, C(═O)NHR
a
, CO
2
R
c
, and heterocycle substituted with 0-5 R
6
;
with the provisos that when R
1
and Het are both 2-pyridinyl, R
2
and R
Singh Jasbir
Tripathy Rabindranath
Cephalon Inc.
Hrubiec Robert T.
Patel Sudhaker R.
Shah Mukund J.
Voelk Eric K.
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