Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-09-19
2003-03-11
Rao, Deepak (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S250000, C514S303000, C514S307000, C514S314000, C514S343000, C514S365000, C514S367000, C514S387000, C514S403000, C514S414000, C514S422000, C514S423000, C544S235000, C544S355000, C546S120000, C546S121000, C546S146000, C546S169000, C546S279100, C548S180000, C548S200000, C548S249000, C548S306100, C548S364100, C548S467000, C548S527000, C548S525000, C548S537000
Reexamination Certificate
active
06531474
ABSTRACT:
TECHNICAL FIELD OF THE INVENTION
The present invention relates to novel classes of compounds which are caspase inhibitors, in particular interleukin-1&bgr; converting enzyme (“ICE”) inhibitors. This invention also relates to pharmaceutical compositions comprising these compounds. The compounds and pharmaceutical compositions of this invention are particularly well suited for inhibiting caspase activity and consequently, may be advantageously used as agents against interleukin-1-(“IL-1”), apoptosis-, interferon-&ggr; inducing factor-(IGIF), or interferon-(“IFN-&ggr;”) mediated diseases, including inflammatory diseases, autoimmune diseases, destructive bone disorders, proliferative disorders, infectious diseases, and degenerative diseases. This invention also relates to methods for inhibiting caspase activity and decreasing IGIF production and IFN-&ggr; production and methods for treating interleukin-1, apoptosis-, and interferon-&ggr;-mediated diseases using the compounds and compositions of this invention. This invention also relates to methods of preparing the compounds of this invention.
BACKGROUND OF THE INVENTION
Interleukin 1 (“IL-1”) is a major pro-inflammatory and immunoregulatory protein that stimulates fibroblast differentiation and proliferation, the production of prostaglandins, collagenase and phospholipase by synovial cells and chondrocytes, basophil and eosinophil degranulation and neutrophil activation. Oppenheim, J. H. et al,
Immunology Today
, 7, pp. 45-56 (1986). As such, it is involved in the pathogenesis of chronic and acute inflammatory and autoimmune diseases. For example, in rheumatoid arthritis, IL-1 is both a mediator of inflammatory symptoms and of the destruction of the cartilage proteoglycan in afflicted joints. Wood, D. D. et al.,
Arthritis Rheum
. 26, 975, (1983); Pettipher, E. J. et al.,
Proc. Natl. Acad. Sci. USA
71, 295 (1986); Arend, W. P. and Dayer, J. M.,
Arthritis Rheum
. 38, 151 (1995). IL-1 is also a highly potent bone resorption agent. Jandiski, J. J.,
J. Oral Path
17, 145 (1988); Dewhirst, F. E. et al.,
J. Immunol
. 8, 2562 1985). It is alternately referred to as “osteoclast activating factor” in destructive bone diseases such as osteoarthritis and multiple myeloma. Bataille, R. et al.,
Int. J. Clin. Lab. Res
. 21(4), 283 (1992). In certain proliferative disorders, such as acute myelogenous leukemia and multiple myeloma, IL-1 can promote tumor cell growth and adhesion. Bani, M. R.,
J. Natl. Cancer Inst
. 83, 123 (1991); Vidal-Vanaclocha, F.,
Cancer Res
. 54, 2667 (1994). In these disorders, IL-1 also stimulates production of other cytokines such as IL-6, which can modulate tumor development (Tartour et al.,
Cancer Res
. 54, p. 6243 (1994). IL-1 is predominantly produced by peripheral blood monocytes as part of the inflammatory response and exists in two distinct agonist forms, IL-1&agr; and IL-1&bgr;. Mosely, B. S. et al.,
Proc. Nat. Acad. Sci
., 84, pp. 4572-4576 (1987); Lonnemann, G. et al.,
Eur. J. Immunol
., 19, pp. 1531-1536 (1989).
IL-1&bgr; is synthesized as a biologically inactive precursor, pIL-1&bgr;. pIL-1&bgr; lacks a conventional leader sequence and is not processed by a signal peptidase. March, C. J.,
Nature
, 315, pp. 641-647 (1985). Instead, pIL-1&bgr; is cleaved by interleukin-1&bgr; converting enzyme (“ICE”) between Asp-116 and Ala-117 to produce the biologically active C-terminal fragment found in human serum and synovial fluid. Sleath, P. R., et al.,
J. Biol. Chem
., 265, pp. 14526-14528 (1992); A. D. Howard et al.,
J. Immunol
., 147, pp. 2964-2969 (1991). ICE is a cysteine protease localized primarily in monocytes. It converts precursor IL-1&bgr; to the mature form. Black, R. A. et al.,
FEBS Lett
., 247, pp. 386-390 (1989); Kostura, M. J. et al.,
Proc. Natl. Acad. Sci. U.S.A
., 86, pp. 5227-5231 (1989). Processing by ICE is also necessary for the transport of mature IL-1&bgr; through the cell membrane.
ICE (or caspase-1) is a member of a family of homologous enzymes called caspases. These homologs have sequence similarities in the active site regions of the enzymes. Such homologs (caspases) include TX (or ICE
rel-II
or ICH-2) (caspase-4) (Faucheu, et al.,
EMBO J
., 14, p. 1914 (1995); Kamens J., et al.,
J. Biol. Chem
., 270, p. 15250 (1995); Nicholson et al.,
J. Biol. Chem
., 270 15870 (1995)), TY (or ICE
rel-III
) (caspase-5) (Nicholson et al.,
J. Biol. Chem
., 270, p. 15870 (1995); ICH-1 (or Nedd-2) (caspase-2) (Wang, L. et al.,
Cell
, 78, p. 739 (1994)), MCH-2 (caspase-6), (Fernandes-Alnemri, T. et al.,
Cancer Res
., 55, p. 2737 (1995), CPP32 (or YAMA or apopain) (caspase-3) (Fernandes-Alnemri, T. et al.,
J. Biol. Chem
., 269, p. 30761 (1994); Nicholson, D. W. et al.,
Nature
, 376, p. 37 (1995)), CMH-1 (or MCH-3) (caspase-7) (Lippke, et al.,
J. Biol. Chem
., 271(4), p 1825-1828 (1996)); Fernandes-Alnemri, T. et al.,
Cancer Res
., (1995)), Mch5 (caspase-8) (Muzio, M. et. al.,
Cell
85(6), 817-827, (1996)), MCH-6 (caspase-9) (Duan, H. et. al.,
J. Biol. Chem
., 271(34), p. 16720-16724 (1996)), Mch4 (caspase-10) (Vincenz, C. et. al.,
J. Biol. Chem
., 272, p. 6578-6583 (1997); Fernandes-Alnemri, T. et. al.,
Proc. Natl. Acad. Sci
. 93, p. 7464-7469 (1996)), Ich-3 (caspase-11) (Wang, S. et. al.,
J. Biol. Chem
., 271, p. 20580-20587 (1996)), mCASP-12 (caspase-12), (Van de Craen, M. et. al.,
FEBS Lett
. 403, p. 61-69 (1997); Yuan, Y. and Miura, M. PCT Publication WO95/00160 (1995)), ERICE (caspase-13), (Humke, E. W., et. al.,
J. Biol. Chem
., 273(25) p. 15702-15707 (1998)), and MICE (caspase-14) (Hu, S. et. al.,
J. Biol. Chem
., 273(45) p. 29648-29653 (1998)).
Each of these ICE homologs, as well as ICE itself, is capable of inducing apoptosis when overexpressed in transfected cell lines. Inhibition of one or more of these homologs with the peptidyl ICE inhibitor Tyr-Val-Ala-Asp-chloromethylketone results in inhibition of apoptosis in primary cells or cell lines. Lazebnik et al.,
Nature
, 371, p. 346 (1994).
Caspases also appear to be involved in the regulation of programmed cell death or apoptosis. Yuan, J. et al.,
Cell
, 75, pp. 641-652 (1993); Miura, M. et al.,
Cell
, 75, pp. 653-660 (1993); Nett-Fiordalisi, M. A. et al.,
J. Cell Biochem
., 17B, p. 117 (1993). In particular, ICE or ICE homologs are thought to be associated with the regulation of apoptosis in neurodegenerative diseases, such as Alzheimer's and Parkinson's disease. Marx, J. and M. Baringa,
Science
, 259, pp. 760-762 (1993); Gagliardini, V. et al.,
Science
, 263, pp. 826-828 (1994). Therapeutic applications for inhibition of apoptosis may include treatment of Alzheimer's disease, Parkinson's disease, stroke, myocardial infarction, spinal atrophy, and aging.
ICE has been demonstrated to mediate apoptosis (programmed cell death) in certain tissue types. Steller, H.,
Science
, 267, p. 1445 (1995); Whyte, M. and Evan, G.,
Nature
, 376, p. 17 (1995); Martin, S. J. and Green, D. R.,
Cell
, 82, p. 349 (1995); Alnemri, E. S., et al.,
J. Biol. Chem
., 270, p. 4312 (1995); Yuan, J.
Curr. Opin. Cell Biol
., 7, p. 211 (1995). A transgenic mouse with a disruption of the ICE gene is deficient in Fas-mediated apoptosis (Kuida, K. et al.,
Science
267, 2000 (1995)). This activity of ICE is distinct from its role as the processing enzyme for pro-IL-1&bgr;. It is conceivable that in certain tissue types, inhibition of ICE may not affect secretion of mature IL-1&bgr;, but may inhibit apoptosis.
Enzymatically active ICE has been previously described as a heterodimer composed of two subunits, p20 and p10 (20 kDa and 10 kDa molecular weight, respectively). These subunits are derived from a 45 kDa proenzyme (p45) by way of a p30 form, through an activation mechanism that is autocatalytic. Thornberry, N. A. et al.,
Nature
, 356, pp. 768-774 (1992). The ICE proenzyme has been divided into several functional domains: a prodomain (p14), a p22/20 subunit, a polypeptide linker and a p10 subunit. Thornberry et al., supra; Casano et al.,
Genomics
, 20, pp. 474-481 (1994).
Full length p45 has been characterized by i
Bemis Guy W.
Charifson Paul S.
Davies Robert J.
Forster Cornelia J.
Grillot Anne-Laure
Fish & Neave
Haley James F.
Rao Deepak
Vertex Pharmaceuticals Incorporated
Wang Min
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