Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-05-17
2002-10-08
Seaman, D. Margaret (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S232800, C514S252190, C514S253090, C514S254060, C514S316000, C514S318000, C514S321000, C514S322000, C514S323000, C514S338000, C514S393000, C540S575000, C544S115000, C544S295000, C544S360000, C544S371000, C546S187000, C546S193000, C546S194000, C546S199000, C546S275700, C548S359100, C548S359500
Reexamination Certificate
active
06462036
ABSTRACT:
This invention relates to certain 3-aryl or 3-heteroaryl pyrazoles with 4,5(3,4)-bicyclic ring fusion which are inhibitors of protein kinases, particularly tyrosine kinases and serine/threonine kinases, of which some are novel compounds, to pharmaceutical compositions containing these pyrazoles and to processes for preparing these pyrazoles.
BACKGROUND OF THE INVENTION
There are at least 400 enzymes identified as protein kinases. These enzymes catalyze the phosphorylation of target protein substrates. The phosphorylation is usually a transfer reaction of a phosphate group from ATP to the protein substrate. The specific structure in the target substrate to which the phosphate is transferred is a tyrosine, serine or threonine residue. Since these amino acid residues are the target structures for the phosphoryl transfer, these protein kinase enzymes are commonly referred to as tyrosine kinases or serine/threonine kinases.
The phosphorylation reactions, and counteracting phosphatase reactions, at the tyrosine, serine and threonine residues are involved in countless cellular processes that underlie responses to diverse intracellular signals (typically mediated through cellular receptors), regulation of cellular functions, and activation or deactivation of cellular processes. A cascade of protein kinases often participate in intracellular signal transduction and are necessary for the realization of these cellular processes. Because of their ubiquity in these processes, the protein kinases can be found as an integral part of the plasma membrane or as cytoplasmic enzymes or localized in the nucleus, often as components of enzyme complexes. In many instances, these protein kinases are an essential element of enzyme and structural protein complexes that determine where and when a cellular process occurs within a cell.
Protein Tyrosine Kinases. Protein tyrosine kinases (PTKs) are enzymes which catalyse the phosphorylation of specific tyrosine residues in cellular proteins. This post-translational modification of these substrate proteins, often enzymes themselves, acts as a molecular switch regulating cell proliferation, activation or differentiation (for review, see Schlessinger and Ulrich, 1992,
Neuron
9:383-391). Aberrant or excessive PTK activity has been observed in many disease states including benign and malignant proliferative disorders as well as diseases resulting from inappropriate activation of the immune system (e.g., autoimmune disorders), allograft rejection, and graft vs. host disease. In addition, endothelial-cell specific receptor PTKs such as KDR and Tie-2 mediate the angiogenic process, and are thus involved in supporting the progression of cancers and other diseases involving inappropriate vascularization (e.g., diabetic retinopathy, choroidal neovascularization due to age-related macular degeneration, psoriasis, arthritis, retinopathy of prematurity, infantile hemangiomas).
Tyrosine kinases can be of the receptor-type (having extracellular, transmembrane and intracellular domains) or the non-receptor type (being wholly intracellular).
Receptor Tyrosine Kinases (RTKs). The RTKs comprise a large family of transmembrane receptors with diverse biological activities. At present, at least nineteen (19) distinct RTK subfamilies have been identified. The receptor tyrosine kinase (RTK) family includes receptors that are crucial for the growth and differentiation of a variety of cell types (Yarden and Ullrich,
Ann. Rev. Biochem.
57:433-478, 1988; Ullrich and Schlessinger,
Cell
61:243-254, 1990). The intrinsic function of RTKs is activated upon ligand binding, which results in phosphorylation of the receptor and multiple cellular substrates, and subsequently in a variety of cellular responses (Ullrich & Schlessinger, 1990,
Cell
61:203-212). Thus, receptor tyrosine kinase mediated signal transduction is initiated by extracellular interaction with a specific growth factor (ligand), typically followed by receptor dimerization, stimulation of the intrinsic protein tyrosine kinase activity and receptor transphosphorylation. Binding sites are thereby created for intracellular signal transduction molecules and lead to the formation of complexes with a spectrum of cytoplasmic signaling molecules that facilitate the appropriate cellular response (e.g., cell division, differentiation, metabolic effects, changes in the extracellular microenvironment); see Schlessinger and Ullrich, 1992,
Neuron
9:1-20.
Proteins with SH2 (src homology-2) or phosphotyrosine binding (PTB) domains bind activated tyrosine kinase receptors and their substrates with high affinity to propagate signals into cells. Both of the domains recognize phosphotyrosine (Fantl, et al., 1992,
Cell
69:413-423; Songyang, et al., 1994,
Mol. Cell. Biol.
14:2777-2785; Songyang, et al., 1993,
Cell
72:767-778; and Koch, et al., 1991,
Science
252:668-678; Shoelson,
Curr. Opin. Chem. Biol.
(1997), 1(2), 227-234; Cowburn,
Curr. Opin. Struct. Biol.
(1997), 7(6), 835-838). Several intracellular substrate proteins that associate with receptor tyrosine kinases (RTKs) have been identified. They may be divided into two principal groups: (1) substrates which have a catalytic domain; and (2) substrates which lack such a domain but serve as adapters and associate with catalytically active molecules (Songyang, et al., 1993,
Cell
72:767-778). The specificity of the interactions between receptors or proteins and SH2 or PTB domains of their substrates is determined by the amino acid residues immediately surrounding the phosphorylated tyrosine residue. For example, differences in the binding affinities between SH2 domains and the amino acid sequences surrounding the phosphotyrosine residues on particular receptors correlate with the observed differences in their substrate phosphorylation profiles (Songyang, et al., 1993,
Cell
72:767-778). Observations suggest that the function of each receptor tyrosine kinase is determined not only by its pattern of expression and ligand availability but also by the array of downstream signal transduction pathways that are activated by a particular receptor as well as the timing and duration of those stimuli. Thus, phosphorylation provides an important regulatory step which determines the selectivity of signalling pathways recruited by specific growth factor receptors, as well as differentiation factor receptors.
Several receptor tyrosine kinases, and growth factors that bind thereto, have been suggested to play a role in angiogenesis, although some may promote angiogenesis indirectly (Mustonen and Alitalo,
J. Cell Biol.
129:895-898, 1995). One such receptor tyrosine kinase, known as “fetal liver kinase 1” (FLK-1), is a member of the type III subclass of RTKs. An alternative designation for human FLK-1 is “kinase insert domain-containing receptor” (KDR) (Terman, et al.,
Oncogene
6:1677-83, 1991). Another alternative designation for FLK-1/KDR is “vascular endothelial cell growth factor receptor 2” (VEGFR-2) since it binds VEGF with high affinity. The murine version of FLK-1/VEGFR-2 has also been called NYK (Oelrichs, et al,
Oncogene
8(1):11-15, 1993). DNAs encoding mouse, rat and human FLK-1 have been isolated, and the nucleotide and encoded amino acid sequences reported (Matthews, et al.,
Proc. Natl. Acad. Sci. USA,
88:9026-30, 1991; Terman, et al., 1991, supra; Terman, et al.,
Biochem. Biophys. Res. Comm.
187:1579-86, 1992; Sarzani, et al., supra; and Millauer, et al.,
Cell
72:835-846, 1993). Numerous studies such as those reported in Millauer, et al., supra, suggest that VEGF and FLK-1/KDR/VEGFR-2 are a ligand-receptor pair that play an important role in the proliferation of vascular endothelial cells, and formation and sprouting of blood vessels, termed vasculogenesis and angiogenesis, respectively.
Another type III subclass RTK designated “fins-like tyrosine kinase-1” (Flt-1) is related to FLK-1/KDR (DeVries, et al.
Science
255;989-991, 1992; Shibuya, et al.,
Oncogene
5:519-524, 1990). An alternative designation for Flt-1 is “vascular endothelial cell growth factor recep
Arnold Lee D.
Doyle Kevin J.
Ericsson Anna M.
Hockley Michael
Iwasaki Nobuhiko
BASF - Aktiengesellschaft
Conway John D.
Seaman D. Margaret
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