Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Reexamination Certificate
2001-09-27
2004-11-16
McKane, Joseph K. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
C546S113000, C546S023000, C514S300000
Reexamination Certificate
active
06818632
ABSTRACT:
The present invention relates generally to novel amine substituted oxindole compounds and compositions having utility as pharmacological agents in treating diseases or conditions alleviated by the inhibition or antagonism of protein kinase activated signalling pathways in general, and in particular in the pathological processes which involve aberrant cellular proliferation, such as tumor growth, restenosis, atherosclerosis, and thrombosis and methods for using and manufacturing such compounds. In particular, the present invention relates to a series of substituted oxindole compounds, which exhibit protein tyrosine kinase and protein serine/threonine kinase inhibition, and which are useful in inhibiting tumor growth via inhibition of tumor-related angiogenesis.
BACKGROUND OF THE INVENTION
Protein kinases play a critical role in the control of cell growth and differentiation and are key mediators of cellular signals leading to the production of growth factors and cytokines. See, for example, Schlessinger and Ullrich,
Neuron
1992, 9, 383. A partial non-limiting list of such kinases includes abl, ARaf, ATK, ATM, bcr-abl, Blk, BRaf, Brk, Btk, CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, cfms, c-fms, c-kit, c-met, cRaf1, CSF1 R, CSK, c-src, EGFR, ErbB2, ErbB3, ErbB4, ERK, ERK1, ERK2, Fak, fes, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, Fgr, FLK-4, Fps, Frk, Fyn, GSK, gsk3a, gsk3b, Hck, IGF-1R, IKK, IKK1, IKK2, IKK3, INS-R, Integrin-linkedkinase, Jak, JAK1, JAK2, JAK3, JNK, JNK, Lck, Lyn, MEK, MEK1, MEK2, p38, PDGFR, PIK, PKB1, PKB2, PKB3, PKC, PKC&agr;, PKC&bgr;, PKC&dgr;, PKC&egr;, PKC&ggr;, PKC&lgr;, PKC&mgr;, PKC&zgr;, PLK1, Polo-like kinase, PYK2, tie1, tie2, TrkA, TrkB, TrkC, UL13, UL97, VEGF-R1, VEGF-R2, Yes and Zap70. Protein kinases have been implicated as targets in central nervous system disorders such as Alzheimer's (Mandelkow, E. M. et al.
FEBS Lett.
1992, 314, 315. Sengupta, A. et al.
Mol. Cell. Biochem.
1997, 167,99), pain sensation (Yashpal, K.
J. Neurosci.
1995, 15, 3263-72), inflammatory disorders such as arthritis (Badger,
J. Pharm. Exp. Ther.
1996, 279, 1453), psoriasis (Dvir, et al,
J. Cell Biol.
1991, 113, 857), and chronic obstructive pulmononary disease, bone diseases such as osteoporosis (Tanaka et al,
Nature,
1996, 383, 528), cancer (Hunter and Pines,
Cell
1994, 79, 573), atherosclerosis (Hajjar and Pomerantz,
FASEB J.
1992, 6, 2933), thrombosis (Salari,
FEBS
1990, 263, 104), metabolic disorders such as diabetes (Borthwick, A. C. et al.
Biochem. Biophys. Res. Commun.
1995, 210, 738), blood vessel proliferative disorders such as angiogenesis (Strawn et al
Cancer Res.
1996, 56, 3540; Jackson et al
J. Pharm. Exp. Ther.
1998, 284, 687), restenosis (Buchdunger et al,
Proc, Nat. Acad. Sci USA
1991, 92, 2258), autoimmune diseases and transplant rejection (Bolen and Brugge,
Ann. Rev. Immunol
1997, 15, 371) and infectious diseases such as viral (Littler, E.
Nature
1992, 358,160), and fungal infections (Lum, R. T. PCT Int. Appl., WO 9805335 A1 980212).
The VEGF-R2 kinase is a receptor tyrosine kinase found in endothelial cells and is involved in angiogenesis—the growth and proliferation of blood vessels from existing capillaries. Angiogenesis plays an important role in development, homeostasis, wound healing, the female reproductive cycle, and in pathological conditions such as rheumatoid arthritis, diabetic retinopathy, macular degeneration, psoriasis and cancer. VEGF-R2 kinase transmits the signal initiated by binding of Vascular Endothelial Growth Factor (VEGF) to the extracellular receptor. Signal transmission to the cell interior is accomplished via tyrosine phosphorylation by VEGF-R2, which prompts proliferation of endothelial cells and the release of cytokines and other cellular processes that result in the growth of new blood vessels. Angiogenesis is critical to the growth of cancerous tumors. Solid tumors will not grow beyond 1-2 mm in size without the support of additional vascularization. Most tumor types, if not all, secrete VEGF in order to stimulate angiogenesis. Inhibition of VEGF-R2 kinase would therefore interrupt a critical process involved in tumor growth and metastasis as well as other pathologic angiogenic conditions.
SUMMARY OF THE INVENTION
In brief summary, the invention comprises compounds of the formula (I):
wherein
Y, Z, A, and D are independently selected from the group consisting of: carbon and nitrogen, with the provisos that: (1) Z and D may be nitrogen, but otherwise no more than one of Y, Z, A, and D may be nitrogen, and (2) when Y, Z, or A are nitrogen, substituent R
1
, R
2
, or R
3
designated for the respective nitrogen atom is non-existent;
X is selected from the group consisting of: N, CH, CCF
3
, and C(C
1-12
aliphatic);
R
1
is selected from the group consisting of: hydrogen, C
1-12
aliphatic, thiol, hydroxy, hydroxy-C
1-12
aliphatic, Aryl, Aryl-C
1-12
aliphatic, R
9
-Aryl-C
1-12
aliphatic, Cyc, Cyc-C
1-6
aliphatic, Het, Het-C
1-12
aliphatic, C
1-12
alkoxy, Aryloxy, amino, C
1-12
aliphatic amino, di-C
1-12
aliphatic amino, di-C
1-12
aliphatic aminocarbonyl, di-C
1-12
aliphatic aminosulfonyl, C
1-12
alkoxycarbonyl, fluoro, bromo, iodo, cyano, sulfonamide, or nitro, where R
9
, Aryl, Cyc and Het are as defined below;
R
2
is selected from the group consisting of: hydrogen, C
1-12
aliphatic, N-hydroxyimino-C
1-12
aliphatic, C
1-12
alkoxy, hydroxy-C
1-12
aliphatic, C
1-12
alkoxycarbonyl, carboxyl C
1-12
aliphatic, Aryl, R
9
-Aryl-oxycarbonyl, R
9
-oxycarbonyl-Aryl, Het, aminocarbonyl, C
1-12
aliphatic-aminocarbonyl, Aryl-C
1-12
aliphatic-aminocarbonyl, R
9
-Aryl-C
1-12
aliphatic-aminocarbonyl, Het-C
1-12
aliphatic-aminocarbonyl, hydroxy-C
1-12
aliphatic-aminocarbonyl, C
1-12
-alkoxy-C
1-12
aliphatic-aminocarbonyl, C
1-12
alkoxy-C
1-12
aliphatic-amino, di-C
1-12
aliphatic amino, di-C
1-12
aliphatic aminocarbonyl, di-C
1-12
aliphatic aminosulfonyl, halogen, hydroxy, C
1-12
aliphatic-sulfonyl, aminosulfonyl, and C
1-12
aliphatic-aminosulfonyl, where R
9
, Aryl and Het are as defined below, with the proviso that where X is nitrogen, R
2
is not chloro or 3,6-dihydro-6-methyl-2-oxo-2H-1,3,4-thiadiazin-5-yl;
R
1
and R
2
are optionally joined to form a fused ring selected from the group as defined for Het below, and said fused ring is optionally substituted by a substituent selected from the group consisting of: C
1-12
aliphatic, halogen, nitro, cyano, C
1-12
alkoxy, amino, hydroxyl, (R
10
, R
11
)-amino, and oxo;
R
3
is selected from the group consisting of: hydrogen, C
1-12
aliphatic, hydroxy, hydroxy C
1-12
aliphatic, di-C
1-12
aliphatic amino, di-C
1-12
aliphatic aminocarbonyl, di-C
1-12
aliphatic aminosulfonyl, C
1-12
alkoxy, Aryl, Aryloxy, hydroxy-Aryl, Het, hydroxy-Het, Het-oxy, or halogen, where Aryl and Het are as defined below, with the proviso that where X is nitrogen R
3
is not fluoro; R
2
and R
3
are optionally joined to form a fused ring selected from the group as defined for Het below, and said fused ring is optionally substituted by C
1-6
aliphatic or C
1-6
aliphatic-carbonyl;
with the proviso that R
1
, R
2
, and R
3
cannot simultaneously be hydrogen;
R
4
, R
5
and R
6
may be the same or different and are independently selected from the group consisting of: hydrogen, C
1-12
aliphatic, thiol, C
1-6
aliphatic-thio, di(trifluoromethyl)hydroxymethyl, carboxamide, mono-C
1-12
aliphatic aminocarbonyl, hydroxy, hydroxy-C
1-12
aliphatic, Aryl, Aryl-C
1-12
aliphatic, R
9
-Aryl-C
1-12
aliphatic, Cyc, Cyc-C
1-6
aliphatic, Het, Het-C
1-12
aliphatic, C
1-12
alkoxy, Aryloxy, Het-oxy, amino, (R
10
,R
11
)-amino-C
1-12
aliphatic aminocarbonyl, (R
10
,R
11
)-amino-C
1-12
aliphatic alkoxycarbonyl, (R
10
,R
11
)-amino-C
1-12
aliphatic aminocarbonylamino, (R
10
,R
11
)-amino-C
1-6
aliphatic alkoxycarbonylamino, (R
10
,R
11
)-amino-C
1-6
aliphaticsulfonyl, Het-C
1-6
aliphatic aminocarbonyl, Het-C
1-6
aliphatic aminocarbonylamino, Het-C
1-6
alkoxycarbonylamino, Het-C
1-6
aliphatic carbonyl, Het-C
1-6
alkoxycarbonyl, C
1-6
aliphaticsulfon
Glennon Kimberley Caroline
Lackey Karen Elizabeth
Lemanowicz John L.
McKane Joseph K.
SmithKline Beecham Corporation
Wright Sonya N.
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