Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-12-21
2003-08-26
Rao, Deepak (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S234500, C514S252160, C514S265100, C544S117000, C544S280000
Reexamination Certificate
active
06610688
ABSTRACT:
1. FIELD OF THE INVENTION
This invention relates to protein kinase inhibitors, pharmaceutical compositions and dosage forms comprising them, and methods of their use for the treatment and prevention of diseases such as, but not limited to, cancer.
2. BACKGROUND OF THE INVENTION
Cellular signal transduction is a mechanism whereby external stimuli that regulate cellular processes are relayed from receptors at the surface of a cell to its interior. One of the key biochemical mechanisms of signal transduction involves the reversible phosphorylation of proteins. The phosphorylation state of a protein, which can affect its conformation, enzymatic activity, and cellular location, is modified through the reciprocal actions of protein kinases (“PKs”) and protein phosphatases. The regulation, or lack of regulation, of protein kinases can thus have a dramatic effect on cellular behavior.
During cellular signal transduction, the function of each receptor kinase is determined by its pattern of expression, ligand availability, and the array of downstream signal transduction pathways that are activated by it. One example of a pathway includes a cascade of Growth Factor receptor tyrosine kinases (“RTKs”), such as EGF-R, PDGF-R, VEGF-R, IGF1-R, and the Insulin receptor, that deliver signals via phosphorylation to other kinases, such as Src tyrosine kinase and Raf, Mek, and Erk serine/threosine kinases. See, e.g., Davis, B. D., et al.,
Microbiology
838-841 (4
th
ed., 1990); and Brott, B. K., et al.,
Cell Growth Differ
. 4(11):921-929 (1993). Each of these kinases play related, but functionally distinct, roles. The loss of regulation of the Growth Factor signaling pathway is a frequent occurrence in disease states such as cancer.
Aberrant expression of, or mutations in, protein kinases have been shown to lead to either uncontrolled cell proliferation (for example, malignant tumour growth) or to defects in key developmental processes. Protein kinases have been implicated as targets in central nervous system disorders (such as Alzheimer's), inflammatory disorders (such as psoriasis), bone diseases (such as osteoporosis), atheroscieroses, restenosis, thrombosis, metabolic disorders (such as diabetes), and infectious diseases (such as viral and fungal infections).
Because the regulation and/or inhibition of protein kinases can aid in the treatment and/or prevention of a variety of diseases, significant research has been directed at discovering compounds that affect protein kinase activity. This research is similar to that which may have led to discovery of the compounds disclosed by PCT application WO 91/09598 and U.S. Pat. No. 5,811,432, which are of the formula
wherein one of A, B, D, and E is nitrogen and the others are carbon; X and Y can be, for example, halogen or hydroxy; R
1
is (C
1
-C
6
) alkyl or an amide; R
2
is (C
1
-C
8
) alkyl, preferably (C
3
-C
8
)alkyl; and W is, for example, hydrogen or (C
2
-C
10
) alkanoyl. These compounds, which are not reported to be kinase inhibitors, are allegedly inhibitors of prostaglandin H
2
synthase, 5-lipoxygenase, and interleukin-1 biosynthesis, and allegedly are anti-inflammatory and analgesic agents.
Examples of compounds that are allegedly protein kinase inhibitors are disclosed by PCT application WO 97/13771. These compounds are of the formula
wherein X is nitrogen or CH; R
2
, Y, R
3
, and R
5
are each selected from a large number of moieties; the group
represents, for example, a 5-membered heterocyclic ring; and each R
1
independently represents a 5- or 6-membered heterocyclic ring.
PCT application WO 98/02437 discloses compounds similar in structure to those described above, i.e.:
As above, R
1
represents a 5- or 6-membered heterocyclic ring. These compounds are also allegedly protein tyrosine kinase inhibitors.
PCT application WO 98/02438 discloses compounds of the formula:
wherein X is nitrogen or CH; R
1
, R
2
, and Y are each selected from a large number of moieties; U is a 5- to 10-membered mono or bicyclic ring system; the group
represents, for example, a 5-membered heterocyclic ring; and R″ represents a phenyl group or a 5- or 6-membered heterocyclic ring. These compounds are also allegedly protein tyrosine kinase inhibitors.
PCT application WO 98/23613 discloses compounds of the formula:
wherein Z can be a group of the formula
and R
6
is H, halogen, cyano, alkyl, or substituted alkyl. These compounds can allegedly be used in the treatment of hyperpoliferative diseases such as cancer.
PCT application WO 99/21859 discloses compounds of the formula:
wherein the R groups are variously defined. These compounds are reportedly useful as protein kinase inhibitors.
PCT application WO 99/37622 discloses a compound of the formula:
which is allegedly useful as a PDE4 and TNF-&agr; antagonist.
U.S. Pat. No. 5,916,891 discloses a compound of the formula:
which is a derivative of the compound of formula:
which is allegedly a p38/Raf inhibitor. Both of these compounds share structural features with rofecoxib, which is sold by Merck under the tradename Vioxx® and which has the formula:
and celecoxib, which is sold by Monsanto and which has the formula:
Final examples of compounds that are allegedly useful as protein kinase inhibitors are disclosed in PCT applications WO 87/04928 and WO 96/16964.
Despite the large number of compounds that reportedly inhibit protein kinase activity, a need still exists for compounds that can be used in the treatment and/or prevention of cancer and other diseases in humans. This is due, in part, to bioavailability, toxicity, and other problems which render many of the known protein kinase inhibitors unsuited for clinical development.
This invention is therefore directed in part to compounds which modulate protein kinase (“PK”) signal transduction by affecting the enzymatic activity of tyrosine kinases and thereby interfering with the signals transduced by them. More particularly, the present invention is directed to compounds which modulate the RTK, cellular tyrosine kinase (“CTK”) and/or serine/threonine kinase (“STK”) mediated signal transduction pathways as a therapeutic approach to treat many kinds of solid tumors, including but not limited to carcinoma, sarcomas including Kaposi's sarcoma, leukemia, erythroblastoma, glioblastoma, meningioma, astrocytoma, melanoma and myoblastoma. Other specific indications related to these include, but are not limited to, brain cancers, bladder cancers, ovarian cancers, gastric cancers, pancreas cancers, colon cancers, blood cancers, lung cancers, bone cancers and leukemias.
Further examples, without limitation, of the types of disorders related to unregulated PK activity that the compounds described herein may be useful in preventing, treating and/or studying, are cell proliferative disorders, fibrotic disorders and metabolic disorders. Cell proliferative disorders, which may be prevented, treated or further studied by the present invention include cancers, blood vessel proliferative disorders and mesangial cell proliferative disorders.
Blood vessel proliferative disorders refer to angiogenic and vasculogenic disorders generally resulting in abnormal proliferation of blood vessels. The formation and spreading of blood vessels, or vasculogenesis and angiogenesis, respectively, play important roles in a variety of physiological processes such as embryonic development, corpus luteum formation, wound healing and organ regeneration. They also play a pivotal role in cancer development. Other examples of blood vessel proliferation disorders include arthritis, where new capillary blood vessels invade the joint and destroy cartilage, and ocular diseases, like diabetic retinopathy, where new capillaries in the retina invade the vitreous, bleed and cause blindness. Conversely, disorders related to the shrinkage, contraction or closing of blood vessels, such as restenosis, are also implicated.
Fibrotic disorders refer to the abnormal formation of extracellular matrices. Examples of fibrotic disorders include hepatic cirrhosis and mesangial cell proliferat
Cui Jingrong
Hirth Klaus Peter
Liang Congxin
McMahon Gerald
Sun Li
Burrous Beth A.
Rao Deepak
Sugen Inc.
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