Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-03-28
2003-02-18
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S252130, C514S312000, C514S313000, C514S314000, C544S106000, C544S111000, C546S001000, C546S153000, C546S159000, C546S160000
Reexamination Certificate
active
06521618
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to 3-cyanoquinoline, 3-cyano-1,6-naphthylidine and 3-cyano-1,7-naphthyridine containing compounds as well as their pharmaceutically acceptable salts. The compounds of the present invention inhibit the activity of protein kinases that are required for cell growth and differentiation. The compounds of this invention are therefore useful for the treatment of certain diseases that result from activity of these protein kinases. The compounds of this invention are anti-cancer agents and are useful for the treatment of cancer in mammals. In addition, the compounds of this invention are useful for the treatment of polycystic kidney disease in mammals. The compounds of this invention may also be used in the treatment of osteoporosis. This invention also relates to the manufacture of said compounds, their use for the treatment of cancer, polycystic kidney disease and osteoporosis, and the pharmaceutical preparations containing them.
2. Description of the Prior Art
Protein kinases are enzymes that catalyze the transfer of a phosphate group from ATP to an amino acid residue, such as tyrosine, serine, threonine, or histidine on a protein. Regulation of these protein kinases is essential for the control of a wide variety of cellular events including proliferation and migration. Specific protein kinases have been implicated in diverse conditions including cancer [Traxler, P. M.,
Exp. Opin. Ther. Patents,
8, 1599 (1998); Bridges, A. J.,
Emerging Drugs,
3, 279 (1998)], restenosis [Mattsson, E.,
Trends Cardiovas. Med.
5, 200 (1995); Shaw,
Trends Pharmacol. Sci.
16, 401 (1995)], atherosclerosis [Raines, E. W.,
Bioessays,
18, 271 (1996)], angiogenesis [Shawver, L. K.,
Drug Discovery Today,
2, 50 (1997); Folkman, J.,
Nature Medicine,
1, 27 (1995)] and osteoporosis [Boyce,
J. Clin. Invest.,
90, 1622 (1992)].
Tyrosine kinases (TKs) are divided into two classes: the non-transmembrane TKs and transmembrane growth factor receptor TKs (RTKs). Growth factors, such as epidermal growth factor (EGF), bind to the extracellular domain of their partner RTK on the cell surface which activates the RTK, initiating a signal transduction cascade that controls a wide variety of cellular responses including proliferation and migration. The overexpression of EGF and also of members of the epidermal growth factor receptor (EGFr) family, which includes EGF-r, erbB-2, erbB-3 and erbB-4, is implicated in the development and progression of cancer [Rusch, V.,
Cytokine Growth Factor Rev.,
7, 133 (1996), Davies, D. E.,
Biochem. Pharmacol.,
51, 1101 (1996) and Modjtahedi, E.,
Int. J. Oncol.,
4, 277 (1994)]. Specifically, over expression of the receptor kinase product of the erbB-2 oncogene has been associated with human breast and ovarian cancers [Slamon, D. J.,
Science,
244, 707 (1989) and Slamon, D. J.,
Science,
235, 177 (1987)]. Upregulation of EGFr kinase activity has been associated with epidermoid tumors [Reiss, M.,
Cancer Res.,
51, 6254 (1991)], breast tumors [Macias, A.,
Anticancer Res.,
7, 459 (1987)], and tumors involving other major organs [Gullick, W. J.,
Brit. Med. Bull.,
47, 87 (1991)].
It is also known that deregulation of EGF receptors is a factor in the growth of epithelial cysts in the disease described as polycystic kidney disease [Du, J.,
Amer. J. Physiol.,
269 (2 Pt 1), 487 (1995); Nauta, J.,
Pediatric Res.,
37(6), 755 (1995); Gattone, V. H.,
Developmental Biology,
169(2), 504 (1995); Wilson, P. D.,
Eur. J. Cell Biol.,
61(1), 131, (1993)]. Compounds which inhibit the catalytic function of the EGF receptors, may consequently be useful for the treatment of this disease.
In addition to EGFr, there are several other RTKs including FGFr, the receptor for fibroblast growth factor (FGF); flk-1, also known as KDR, and flt-1, the receptors for vascular endothelial growth factor (VEGF); and PDGFr, the receptor for platelet derived growth factor (PDGF). The formation of new blood vessels, a process known as angiogenesis, is essential for tumor growth. Two natural angiogenesis inhibitors, angiostatin and endostatin, dramatically inhibited the growth of a variety of solid tumors. [O'Reilly, M. S.,
Cell,
79, 315 (1994); O'Reilly, M. S.,
Nature Medicine,
2, 689 (1996); O'Reilly, M. S.,
Cell,
88, 277 (1997)]. Since FGF and VEGF are known to stimulate angiogenesis, inhibition of the kinase activity of their receptors should block the angiogenic effects of these growth factors. In addition, the receptor tyrosine kinases tie-1 and tie-2 also play a key role in angiogenesis [Sato, T. N.,
Nature,
376, 70 (1995)]. Compounds that inhibit the kinase activity of FGFr, flk-1, flt-1, tie-1 or tie-2 may inhibit tumor growth by their effect on angiogenesis.
PDGF is a potent growth factor and chemoattractant for smooth muscle cells (SMCs) and the renarrowing of coronary arteries following angioplasty is due in part to the enhanced proliferation of SMCs in response to increased levels of PDGF. Therefore, compounds that inhibit the kinase activity of PDGFr may be useful in the treatment of restenosis. In addition, since PDGF and PDGFr are overexpressed in several types of human gliomas, small molecules capable of suppressing PDGFr activity, have potential utility as anticancer therapeutics [Nister, M.,
J. Biol. Chem.
266, 16755 (1991); Strawn, L. M.,
J. Biol. Chem.
269, 21215 (1994)].
Other RTKs that could potentially be inhibited by compounds of this invention include colony stimulating factor receptor, the nerve growth factor receptors (trkA, trkB and trkC), the insulin receptor, the insulin-like growth factor receptor, the hepatocyte growth factor receptor and the erythropoietin-producing hepatic cell receptor (EPH).
In addition to the RTKs there is another family of TKs termed the cytoplasmic protein or non-receptor TKs. The cytoplasmic protein TKs have intrinsic kinase activity, are present in the cytoplasm and nucleus, and participate in diverse signaling pathways. There are a large number of non-receptor TKs including Abl, Jak, Fak, Syk, Zap-70 and Csk. However, the major family of cytoplasmic protein TKs is the Src family which consists of at least eight members (Src, Fyn, Lyn, Yes, Lck, Fgr, Hck and Blk) that participate in a variety of signaling pathways [Schwartzberg, P. L.,
Oncogene,
17, 1463 (1998)]. The prototypical member of this tyrosine kinase family is Src, which is involved in proliferation and migration responses in many cell types. Src activity has been shown to be elevated in breast, colon (~90%), pancreatic (>90%) and liver (>90%) tumors. Greatly increased Src activity is also associated with metastasis (>90%) and poor prognosis. Antisense Src message impedes growth of colon tumor cells in nude mice [Staley, C. A.,
Cell Growth Differentiation,
8, 269 (1997)], suggesting that Src inhibitors should slow tumor growth. In addition to its role in cell proliferation, Src also acts in stress response pathways, including the hypoxia response. Nude mice studies with colon tumor cells expressing antisense Src message have reduced vascularization [Ellis, L. M.,
J. Biol. Chem.,
273, 1052 (1998)], which suggests that Src inhibitors would be anti-angiogenic as well as anti-proliferative.
In addition to its role in cancer, Src also appears to play a role in osteoporosis. Mice genetically engineered to be deficient in Src production were found to exhibit osteopetrosis, the failure to resorb bone [Soriano, P.,
Cell,
64, 693 (1991); Boyce, B. F.,
J. Clin., Invest.,
90, 1622 (1992)]. This defect was characterized by a lack of osteoclast activity. Since osteoclasts normally express high levels of Src, inhibition of Src kinase activity may be useful in the treatment of osteoporosis [Missbach, M.,
Bone,
24, 437 (1999)].
Two members of the cytoplasmic protein TKs, lck and ZAP-70 are predo
Berger Dan Maarten
Boschelli Diane Harris
Boschelli Frank Charles
DeMorin Frenel Fils
Overbeek-Klumpers Elsebe Geraldine
Moran Daniel B.
Patel Sudhaker B.
Wyeth
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