Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1996-06-04
1998-02-03
Dees, Jose G.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514252, 514253, 514254, 514249, 514248, 5142305, A61K 31505
Patent
active
057144931
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to the modulation and/or inhibition of cell signaling, cell proliferation, the control of abnormal cell growth and cell inflammatory response. More specifically, this invention relates to the use of mono- and/or bicyclic aryl or heteroaryl quinazoline compounds which exhibit selective inhibition of differentiation, proliferation or mediator release by effectively inhibiting CSF-1R tyrosine kinase activity.
Normal cell growth is believed to be triggered by the exposure of the cellular substrate to one or more growth factors, examples of which are insulin, epidermal growth factor (EGF) and platelet-derived growth factor (PDGF). Receptors for such growth factor are imbedded in and penetrate through the cellular membrane. The initiation of cellular reproduction is believed to occur when a growth factor binds to the corresponding receptor on the external surface of the cellular membrane. This growth factor-receptor binding alters the chemical characteristics of that portion of the receptor which exists within the cell and which functions as an enzyme to catalyze phosphorylation of either an intracellular substrate or the receptor itself, the latter being referred to as autophosphorylation. Examples of such phosphorylating enzymes include tyrosine kinases, which catalyze phosphorylation of tyrosine amino acid residues of substrate proteins.
Many disease states are characterized by the uncontrolled growth of cells. These disease states involve a variety of cell types and include disorders such as cancer, leukemia, psoriasis, inflammatory diseases, bone diseases, atherosclerosis and restenosis occuring subsequent to angioplastic procedures. The inhibition of tyrosine kinases is believed to have utility in the control of deregulated cellular proliferation, i.e., cellular proliferative disorders.
Initiation of autophosphorylation, i.e., phosphorylation of the growth factor receptor itself, and of the phosphorylation of a host of intracellular substrates are some of the biochemical events which are involved in mediator release and cell proliferation.
REPORTED DEVELOPMENTS
Inhibitors of p56.sup.Ick tyrosine kinase have been reported in the literature by Bolen, J. B. et al. FASEB J. 1992, 3403., Mustelin, T. et al. TIBS 1993,215.; Eichmann, K. Angew. Chem. Int. Ed. Eng. 1993, 54.; and Klausner, R. D. Samelson, L. E. Cell 1991 , 875. These include compounds that are potent but nonselective inhibitors, such as staurosporine, which is competitive with ATP or compounds that are very weak tyrosine kinase inhibitors, but are somewhat selective, such as the flavonoid quercetin.
A series of dihydroxy-isoquinolines have been been reported by Burke, T. R. et al. (Biorg. & Med. Chem. Lett. 1992, 1771; J. Med. Chem. 1993 3010 and J. Med. Chem. 1993,3015) that have potent p56.sup.Ick inhibiting activity. Potential therapeutic uses for selective inhibitors of p56.sup.Ick include the treatment of autoimmune diseases such as rheumatoid arthritis or transplant rejection.
p56.sup.Ick, which is a non-receptor tyrosine kinase, has been shown to be important in intracellular signaling in T-cells. It is assumed that inhibitors of p56.sup.Ick kinase activity perturb the activation of T-cells and therefore a selective inhibitor could prove useful in the treatment of T-cell mediated conditions such as organ rejection, rheumatoid arthritis or other auto-immune diseases.
SUMMARY OF THE INVENTION
The present invention describes compounds which are inhibitors of the colony stimulating factor-1 receptor tyrosine kinase, CSF-1R, activity and have activity in a p56.sup.Ick cell-free assay. These compounds do not appear to have any significant serine/threonine kinase inhibitory activity and in addition, compounds within the scope of this invention do not demonstrate significant PDGF-R activity in a cell-free assay. Compounds of this invention are also weak inhibitors of PDGF-induced mitogenesis which may suggest that these compounds inhibit other src-like tyrosine kina
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Hsu Chin-Yi Jenny
Johnson Susan E.
Maguire Martin P.
Myers Michael R.
Persons Paul E.
Cebuilak Mary C.
Dees Jos,e G.
Nicholson James A.
Parker III Raymond S.
Rhone-Poulenc Rorer Pharmaceuticals Inc.
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