Tricyclic protein kinase inhibitors

Details Tricyclic protein kinase inhibitors Tricyclic protein kinase inhibitors

2000-12-29

2003-10-28

Solola, Taopiq (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S253030, C514S290000, C544S259000, C544S126000, C544S361000, C546S101000, C546S160000

Reexamination Certificate

active

06638929

ABSTRACT:

BACKGROUND OF THE INVENTION
This invention relates to substituted aromatic tricyclic compounds containing nicotinonitrile rings as well as the pharmaceutically acceptable salts thereof The compounds of the present invention inhibit the action of certain protein kinases, thereby inhibiting the abnormal growth of particular cell types. The compounds of this invention are therefore useful for the treatment or inhibition of certain diseases that are the result of deregulation of these protein kinases. The compounds of this invention are anti-cancer agents and are useful for the treatment or inhibition of cancer in mammals. In addition, the compounds of this invention are useful for the treatment and inhibition of polycystic kidney disease and colonic polyps.
Protein kinases are a class of enzymes that catalyze the transfer of a phosphate group from ATP to a tyrosine, serine, threonine, or histidine residue located on a protein substrate. Protein kinases clearly play a role in normal cell growth. Many of the growth factor receptor proteins function as kinases and it is by this process that they effect signaling. The interaction of growth factors with these receptors is a necessary event in normal regulation of cell growth. However, under certain conditions, as a result of either mutation or over expression, these receptors can become deregulated; the result of which is uncontrolled cell proliferation which can lead to tumor growth and ultimately to the disease known as cancer [Wilks, A. F.,
Adv. Cancer Res.,
60, 43 (1993) and Parsons, J. T.; Parsons, S. J.,
Important Advances in Oncology,
DeVita, V. T. Ed., J. B. Lippincott Co., Phila., 3 (1993)]. Among the growth factor receptor kinases and their proto-oncogenes that have been identified and which are targets of the compounds of this invention are the epidermal growth factor receptor kinase (EGF-R kinase, the protein product of the erbB oncogene), and the product produced by the erbB-2 (also referred to as the neu or HER2) oncogene. Since the phosphorylation event is a necessary signal for cell division to occur and since overexpressed or mutated kinases have been associated with cancer, an inhibitor of this event, a protein tyrosine kinase inhibitor, will have therapeutic value for the treatment of cancer and other diseases characterized by uncontrolled or abnormal cell growth. For example, over expression of the receptor kinase product of the erbB-2 oncogene has been associated with human breast and ovarian cancers [Slamon, D. J. et al.,
Science,
244, 707 (1989) and
Science,
235 , 177 (1987)]. Deregulation of EGF-R kinase has been associated with epidermoid tumors [Reiss, M., et al.,
Cancer Res.,
51, 6254 (1991)], breast tumors [Macias, A. et al.,
Anticancer Res.,
7, 459 (1987)], and tumors involving other major organs [Gullick, W. J.,
Brit. Med. Bull.,
47, 87 (1991)]. Because of the importance of the role played by deregulated receptor kinases in the pathogenesis of cancer, many recent studies have dealt with the development of specific PTK inhibitors as potential anti-cancer therapeutic agents [some recent reviews: Traxler, P.,
Exp. Opin. Ther. Patents,
8, 1599 (1998) and Bridges, A. J.,
Emerging Drugs,
3, 279 (1998)].
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., Wilson, P. D.,
Amer. J. Physiol.,
269 (2 Pt 1), 487 (1995); Nauta, J., et al.,
Pediatric Research,
37(6), 755 (1995); Gattone, V. H. et al.,
Developmental. Biology,
169(2), 504 (1995); Wilson, P. D. et al.,
Eur. J. Cell Biol.,
61(1), 131, (1993)]. The compounds of this invention, which inhibit the catalytic function of the EGF receptors, are consequently useful for the treatment of this disease.
The mitogen-activated protein kinase (MAPK) pathway is a major pathway in the cellular signal transduction cascade from growth factors to the cell nucleus. The pathway involves kinases at two levels: MAP kinase kinases (MAPKK), and their substrates MAP kinases (MAPK). There are different isoforms in the MAP kinase family. (For review, see Seger, R.; Krebs, E. G.,
FASEB,
9, 726, (1995).) The compounds of this invention can inhibit the action of two of these kinases: MEK, a MAP kinase kinase, and its substrate ERK, a MAP kinase. MEK is activated by phosphorylation on two serine residues by upstream kinases such as members of the raf family. When activated, MEK catalyzes phosphorylation on a threonine and a tyrosine residue of ERK. The activated ERK then phosphorylates and activates transcription factors in the nucleus, such as fos and jun, or other cellular targets with PXT/SP sequences. ERK, a p42 MAPK, is found to be essential for cell proliferation and differentiation. Over-expression and/or over-activation of MEK or ERK has been found to be associated with various human cancers [For example, Sivaraman, V. S.; Wang, H-Y.; Nuovo, G. J. Malbon, C. C. J. Clin. Invest., 99, 1478 (1997)]. It has been demonstrated that inhibition of MEK prevents activation of ERK and subsequent activation of ERK substrates in cells, resulting in inhibition of cell growth stimulation and reversal of the phenotype of ras-transformed cells [Dudley, D. T.; Pang, L.; Decker, S. J.; Bridges, A. J.; Saltiel, A. R.,
Proc. Nat. Acad. Sci.,
92, 7686, (1995)]. Since, as demonstrated below, the compounds of this invention can inhibit the coupled action of MEK and ERK, they are useful for the treatment of diseases such as cancer which are characterized by uncontrolled cell proliferation and which, at least in part, depend on the MAPK pathway.
As mentioned above, members of the raf family of kinases phosphorylate serine residues on MEK. There are three serine/threonine kinase members of the raf family known as a-raf, b-raf and c-raf. While mutations in the raf genes are rare in human cancers, c-raf is activated by the ras oncogene which is mutated in a wide number of human tumors. Therefore inhibition of the kinase activity of c-raf may provide a way to prevent ras mediated tumor growth [Campbell, S. L.,
Oncogene,
17, 1395 (1998)].
The Src family of cytoplasmic protein tyrosine kinases 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, 1463-1468, (1998)]. The prototypical member of this tyrosine kinase family is p60
src
(Src). Src is involved in proliferation and migration responses in many cell types. In limited studies, 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 et al.,
Cell Growth
&
Differentiation.,
8, 269-74, (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, and nude mice studies with colon tumor cells expressing antisense Src message have reduced vascularization [Ellis, et al.,
J. Biol. Chem.,
273, 1052-7 (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)].
In addition to EGFr, there are several other RTKs including FGFr, the receptor

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