Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-03-22
2004-02-10
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S414000, C514S415000, C548S468000, C548S465000, C548S466000, C548S486000
Reexamination Certificate
active
06689806
ABSTRACT:
BACKGROUND OF THE INVENTION
The following description of the background of the invention is provided to aid in understanding the invention, but is not admitted to describe or constitute prior art to the invention.
Protein kinases (“PKs”) are enzymes that catalyze the phosphorylation of hydroxy groups on tyrosine, serine and threonine residues of proteins. The consequences of this seemingly simple activity are staggering. Cell growth, differentiation and proliferation, i.e., virtually all aspects of cell life, in one way or another depend on PK activity. Furthermore, abnormal PK activity has been related to a host of disorders, ranging from relatively non-life-threatening diseases such as psoriasis to extremely virulent diseases such as glioblastoma (brain cancer).
The PKs can conveniently be broken down into two classes, the protein tyrosine kinases (PTKs) and the serine-threonine kinases (STKs).
One of the prime aspects of PK activity is involvement with growth factor receptors. Growth factor receptors are cell-surface proteins. When bound by a growth factor ligand, growth factor receptors are converted to an active form that can interact with proteins on the inner surface of a cell membrane. This interaction leads to phosphorylation on tyrosine residues of the receptor as well as other amino acids and to the formation inside the cell of complexes with a variety of cytoplasmic signaling molecules. In turn, these complexes affect numerous cellular responses such as cell division (proliferation), cell differentiation, cell growth, expression of metabolic effects on the extracellular microenvironment, etc. For a more complete discussion, see Schlessinger and Ullrich,
Neuron
, 1992, 9:303-391 which is incorporated by reference, including any drawings, as if fully set forth herein.
Receptor tyrosine kinases (RTKs) are growth factor receptors with PK activity. They comprise a large family of transmembrane receptors with diverse biological activity. At present, at least nineteen (19) distinct subfamilies of RTKs have been identified. An example of these is the subfamily designated the “HER” RTKs, which includes EGFR (epithelial growth factor receptor), HER2, HER3 and HER4. These RTKs consist of an extracellular glycosylated ligand binding domain, a transmembrane domain and an intracellular cytoplasmic catalytic domain that can phosphorylate tyrosine residues on proteins.
Another RTK subfamily consists of insulin receptor (IR), insulin-like growth factor I receptor (IGF-1R) and insulin receptor related receptor (IRR). IR and IGF-1R interact with insulin, IGF-I and IGF-II to form a heterotetramer composed of two entirely extracellular glycosylated &agr; subunits and two &bgr; subunits which contain the tyrosine kinase domain.
A third RTK subfamily is referred to as the platelet derived growth factor receptor (“PDGFR”) group, which includes PDGFR&agr;, PDGFR&bgr;, CSFIR, c-kit and c-fms. These receptors consist of a glycosylated extracellular domain composed of variable numbers of immunoglobin-like loops, a transmembrane domain and an intracellular domain having a tyrosine kinase domain interrupted by unrelated amino acid sequences.
Another group which, because of its similarity to the PDGFR subfamily, is sometimes subsumed in the latter group, is the fetus liver kinase (“flk”) receptor subfamily. This group is believed to be composed of kinase insert domain-receptor fetal liver kinase-1 (KDR/FLK-1), flk-1R, flk-4 and fms-like tyrosine kinase 1 (flt-1).
One further member of the tyrosine kinase growth factor receptor family is the fibroblast growth factor (“FGF”)receptor group. This group consists of four receptors, FGFR1-4, and seven ligands, FGF1-7. While not yet well characterized, it appears that the receptors also consist of a glycosylated extracellular domain containing a variable number of immunoglobin-like loops, a transmembrane domain and an intracellular domain in which the tyrosine kinase domain is interrupted by regions of unrelated amino acid sequences.
A more complete listing of the known RTK subfamilies is described in Plowman et al.,
DN
&
P
, 1994, 7(6):334-339 which is incorporated by reference, including any drawings, as if fully set forth herein.
In addition to the RTKs, there also exists a family of entirely intracellular PTKs called “non-receptor tyrosine kinases” or “cellular tyrosine kinases” (“CTK”). CTKs do not contain extracellular and transmembrane domains. At present, over 24 CTKs in 11 subfamilies (Src, Frk, Btk, Csk, Abl, Zap70, Fes, Fps, Fak, Jak and Ack) have been identified. The Src subfamily appears so far to be the largest group of CTKs and includes Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr and Yrk. For a more detailed discussion of CTKs, see Bolen,
Oncogene
, 1993, 8:2025-2031, which is incorporated by reference, including any drawings, as if fully set forth herein.
The serine-threonine kinases or STKs, like the CTKs, are predominantly intracellular although there are a few STK receptor kinases. STKs are the most common of the cytosolic kinases; i.e., kinases that perform their function in that part of the cytoplasm other than the cytoplasmic organelles and cytoskelton. The cytosol is the region within the cell where much of the cell's intermediary metabolic and biosynthetic activity occurs; e.g., it is in the cytosol that proteins are synthesized on ribosomes.
RTKs, CTKs and STKs have all been implicated in a host of pathogenic conditions including, significantly, cancer. Other pathogenic conditions which have been associated with PTKs include, without limitation, psoriasis, hepatic cirrhosis, diabetes, atherosclerosis, angiogenesis, restenosis, ocular diseases, rheumatoid arthritis and other inflammatory disorders, immunological disorders such as autoimmune disease, cardiovascular diseases such as atherosclerosis and a variety of renal disorders.
With regard to cancer, two of the major hypotheses advanced to explain the excessive cellular proliferation that drives tumor development relate to functions known to be PK regulated. That is, it has been suggested that malignant cell growth is the result of a breakdown in the mechanisms that control cell division and/or differentiation. It has been shown that the protein products of a number of proto-oncogenes are involved in the signal transduction pathways that regulate cell growth and differentiation. These protein products of proto-oncogenes include the extracellular growth factors, transmembrane growth factor PTK receptors (RTKs), cytoplasmic PTKs (CTKs) and cytosolic STKs, discussed above.
In view of the apparent link between PK-related cellular activities and a number of human disorders, it is no surprise that a great deal of effort is being spent to identify ways to modulate PK activity. Some of these efforts have been directed at biomimetic approaches using large molecules patterned on those involved in the actual cellular processes (e.g., mutant ligands (U.S. Pat. No. 4,966,849); soluble receptors and antibodies (App. No. WO 94/10202, Kendall and Thomas,
Proc. Nat'l Acad. Sci
., 1994, 90:10705-09, Kim, et al.,
Nature
, 1993, 362:841-844); RNA ligands (Jelinek, et al.,
Biochemistry
, 33:10450-56); Takano, et al.,
Mol. Bio. Cell
, 1993, 4:358A; Kinsella, et al.,
Exp. Cell Res
., 1992, 199:56-62; Wright, et al.,
J. Cellular Phys
., 152:448-57) and tyrosine kinase inhibitors (WO 94/03427; WO 92/21660; WO 91/15495; WO 94/14808; U.S. Pat. No. 5,330,992; Mariani, et al.,
Proc. Am. Assoc. Cancer Res
., 1994, 35:2268).
More recently, attempts have been made to identify small molecules that act as PK inhibitors. For example, bis-monocylic, bicyclic and heterocyclic aryl compounds (PCT WO 92/20642), vinylene-azaindole derivatives (PCT WO 94/14808) and 1-cyclopropyl-4-pyridylquinolones (U.S. Pat. No. 5,330,992) have been described as PTK inhibitors. Styryl compounds (U.S. Pat. No. 5,217,999), styryl-substituted pyridyl compounds (U.S. Pat. No. 5,302,606), quinazoline derivatives (EP App. No. 0 566 266 A1), selenaindoles and selenides (PCT WO 94/03427), tricyclic polyhydroxylic compounds (P
Harris, Jr. G. Davis
Li Xiaoyuan
Liang Congxin
McMahon Gerald
Miller Todd Anthony
Burrous Beth A.
Foley & Lardner
Patel Sudhaker B.
Shah Mukund J.
Sugen Inc.
LandOfFree
Indolinone compounds as 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 Indolinone compounds as kinase inhibitors, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Indolinone compounds as kinase inhibitors will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3287132