Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
2000-08-25
2003-07-22
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S613000, C514S715000, C514S730000, C544S106000, C544S162000, C544S170000, C564S080000, C564S084000, C564S100000, C564S123000, C564S430000, C568S021000, C568S038000, C568S579000, C568S608000
Reexamination Certificate
active
06596772
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to, inter alia, novel trifluoromethyl sulfonyl and trifluoromethyl sulfonamido compounds, their physiologically acceptable salts and prodrugs, which modulate the activity of protein phosphatases and uses thereof. The invention also relates to the use of compounds containing fluoromethyl sulfonyl groups to treat certain diseases. These compounds may be used as phosphate mimics to inhibit, regulate or modulate the activity of a phosphate binding protein in a cell. Thus, these mimics may be particularly useful in the treatment of phosphate binding protein associated disorders.
BACKGROUND OF THE INVENTION
Phosphate derivatives are involved in a wide variety of cellular processes. Common phosphate derivatives include nucleotides (e.g. mono-, di- or tri-phosphate adenosine, guanine, cytosine, thymidine, or uridine, or cyclic derivatives) either naturally occurring or synthetic analogues. Other common cellular phosphate derivatives include co-factors such as thiamine pyrophosphate, NADPH, pyridoxal pyrophosphate, or coenzyme A; compounds involved in sugar metabolism such as glucose 6-phosphate, fructose 6-phosphate, compounds involved in fatty acid metabolism such as glycerol 3-phosphate; compounds involved in lipid biosynthesis such as isopentyl pyrophosphate, geranyl pyrophosphate or farnesyl pyrophosphate.
Signal Transduction
Another area involving phosphate binding proteins is cellular transduction. Cellular signal transduction is a fundamental mechanism whereby external stimuli that regulate diverse cellular processes are relayed to the interior of cells. The biochemical pathways through which signals are transmitted within cells comprise a circuitry of directly or functionally connected interactive proteins. One of the key biochemical mechanisms of signal transduction involves the reversible phosphorylation of residues on proteins. The phosphorylation state of a protein may affect its conformation and/or enzymatic activity as well as its cellular location. The phosphorylation state of a protein is modified through the reciprocal actions of protein kinases and protein phosphatases at various specific residues.
A common mechanism by which receptors regulate cell function is through an inducible kinase or phosphatase activity, including tyrosine kinase activity which is either endogenous to the receptor or is imparted by other proteins that become associated with the receptor. (Darnell et al., 1994, Science, 264:1415-1421; Heldin, 1995, Cell, 80:213-223; Pawson, 1995, Nature, 373:573-580). Protein tyrosine kinases (PTK) comprise a large family of transmembrane receptor and intracellular enzymes with multiple functional domains (Taylor et al., 1992, Ann. Rev. Cell Biol. 8:429-62). The binding of ligand allosterically transduces a signal across the cell membrane where, the cytoplasmic portion of the PTKs initiates a cascade of molecular interactions that disseminate the signal throughout the cell and into the nucleus. Many receptor protein tyrosine kinase (RTKs), such as epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor (PDGFR) undergo oligomerization upon ligand binding, and the receptors self-phosphorylate (via autophosphorylation or transphosphorylation) on specific tyrosine residues in the cytoplasmic portions of the receptor (Schlessinger and Ullrich, 1992, Neuron, 9:383-91, Heldin, 1995, Cell, 80:213223). Cytoplasmic protein tyrosine kinases (CTKs), such as Janus kinases (e.g., JAK1, JAK2, TYK2) and Src kinases (e.g., src, lck, fyn) are associated with receptors for cytokines (e.g., IL-2, IL-3, IL-6, erythropoietin), interferons and antigens. These associated receptors also undergo oligomerization, and have tyrosine residues that become phosphorylated during activation, but the receptor polypeptides themselves do not possess kinase activity.
Like the PTKS, the protein tyrosine phosphatases (PTPs) comprise a family of transmembrane and cytoplasmic enzymes, possessing at least an approximately 230 amino acid catalytic domain containing a highly conserved active site with the consensus motif [I/V]HCXXXXXR[S/T] (SEQ ID NO: 1). The substrates of PTPs may be PTKs which possess phosphotyrosine residues or the substrates of PTKs. (Hunter, 1989, Cell, 58:1013-16; Fischer et al., 1991, Science, 253:401-6; Saito and Streuli, 1991, Cell Growth and Differentiation, 2:59-65; Pot and Dixon, 1992, Biochem. Biophys. Acta, 1136:35-43).
Transmembrane or receptor-like PTPs (RTPs) possess an extracellular domain, a single transmembrane domain, and one or two catalytic domains followed by a short cytoplasmic tail. The extracellular domains of these RTPs are highly divergent, with small glycosylated segments (e.g., RTP&agr;, RTP&egr;), tandem repeats of immunoglobulin-like and/or fibronectin type III domains (e.g., LAR) or carbonic anhydrase like domains (e.g., RTP&agr;, RTP&bgr;). These extracellular features might suggest that these RTPs function as a receptor on the cell surface, and their enzymatic activity might be modulated by ligands. Intracellular or cytoplasmic PTPs (CTPs), such as PTP1C and PTP1D, typically contain a single catalytic domain flanked by several types of modular conserved domains. For example, PTP1C, a hemopoietic cell CTP, is characterized by two Src homology 2 (SH2) domains that recognize short peptide motifs bearing phosphotyrosine (pTyr).
In general, these modular conserved domains may influence the intracellular localization of the protein. SH2-domain containing proteins are able to bind pTyr sites in activated receptors and cytoplasmic phosphoproteins. Another conserved domain known as SH3 binds to proteins with proline-rich regions. A third type known as the pleckstrin-homology (PH) domain has also been identified. These modular domains have been found in both CTKs and CTPs as well as in noncatalytic adapter molecules, such as Grbs (Growth factor Receptor Bound), which mediate protein-protein interactions between components of the signal transduction pathway (Skolnik et al., 1991, Cell, 65:83-90; Pawson, 1995, Nature, 373:573-580).
Multiprotein signaling complexes comprising receptor subunits, kinases, phosphatases and adapter molecules are assembled in subcellular compartments through the specific and dynamic interactions between these domains and their binding motifs. Such signaling complexes integrate the extracellular signal with the ligand-bound receptor and relay the signal to other downstream signaling proteins or complexes in other locations inside the cell, including the nucleus (Koch et al., 1991, Science, 252:668-674; Pawson, 1994, Nature, 373:573-580; Mauro et al., 1994, Trends Biochem. Sci., 19:151-155; Cohen et al., 1995, Cell, 80:237-248).
The levels of phosphorylation required for normal cell growth and differentiation at any time are achieved through the coordinated action of phosphatases and kinases. Depending on the cellular context, these two types of enzymes may either antagonize or cooperate with each other during signal transduction. An imbalance between these enzymes may impair normal cell functions leading to metabolic disorders and cellular transformation.
For example, insulin binding to the insulin receptor, which is a PTK, triggers a variety of metabolic and growth promoting effects such as glucose transport, biosynthesis of glycogen and fats, DNA synthesis, cell division and differentiation. Diabetes mellitus, which is characterized by insufficient or a lack of insulin signal transduction, can be caused by any abnormality at any step along the insulin signaling pathway. (Olefsky, 1988, “Cecil Textbook of Medicine,” 18th Ed., 2:1360-81).
It is also well known, for example, that the overexpression of PTKS, such as HER2, can play a decisive role in the development of cancer (Slamon et al., 1987, Science, 235:77-82) and that antibodies capable of blocking the activity of this enzyme can abrogate tumor growth (Drebin et al., 1988, Oncogene, 2:387-394). Blocking the signal transduction capability of tyrosine kinases such as FlK-1 and the PD
Biltz John
Huang Ping
Jallal Bahija
Koenig Marcel
Li Sharon
Burrous Beth A.
Patel Sudhaker B.
Raymond Richard L.
Sugen Inc.
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