Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
2000-12-19
2002-12-10
Travers, Russell (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
active
06492425
ABSTRACT:
FIELD OF THE INVENTION
This invention relates in general to salicylanilide inhibitors of transcription factor NF-&kgr;B. Such compounds are particularly useful for treating diseases in which activation of NF-&kgr;B is implicated. More specifically, these compounds inhibit I&kgr;B phosphorylation and subsequent degradation. Such compounds are useful in the treatment of a variety of diseases associated with NF-&kgr;B activation including inflammatory disorders; particularly rheumatoid arthritis, inflammatory bowel disease, and asthma; dermatosis, including psoriasis and atopic dermatitis; autoimmune diseases; tissue and organ rejection; Alzheimer's disease; stroke; atherosclerosis; restenosis; cancer, including Hodgkins disease; and certain viral infections, including AIDS; osteoarthritis; osteoporosis; and Ataxia Telangiestasia.
BACKGROUND OF THE INVENTION
Recent advances in scientific understanding of the mediators involved in acute and chronic inflammatory diseases and cancer have led to new strategies in the search for effective therapeutics. Traditional approaches include direct target intervention such as the use of specific antibodies, receptor antagonists, or enzyme inhibitors. Recent breakthroughs in the elucidation of regulatory mechanisms involved in the transcription and translation of a variety of mediators have led to increased interest in therapeutic approaches directed at the level of gene transcription.
NF-&kgr;B belongs to a family of closely related dimeric transcription factor complexes composed of various combinations of the Rel/NF-&kgr;B family of polypeptides. The family consists of five individual gene products in mammals, RelA (p65), NF-&kgr;B1 (p50/p105), NF-&kgr;B2 (p49/p100), c-Rel, and RelB, all of which can form hetero- or homodimers. These proteins share a highly homologous 300 amino acid “Rel homology domain” which contains the DNA binding and dimerization domains. At the extreme C-terminus of the Rel homology domain is a nuclear translocation sequence important in the transport of NF-&kgr;B from the cytoplasm to the nucleus. In addition, p65 and cRel possess potent transactivation domains at their C-terminal ends.
The activity of NF-&kgr;B is regulated by its interaction with a member of the inhibitor I&kgr;B family of proteins. This interaction effectively blocks the nuclear localization sequence on the NF-&kgr;B proteins, thus preventing-migration-of the dimer to the nucleus. A wide variety of stimuli activate NF-&kgr;B through what are likely to be multiple signal transduction pathways. Included are bacterial products (LPS), some viruses (HIV-1, HTLV-1), inflammatory cytokines (TNF&agr;, IL-1), and environmental stress. Apparently common to all stimuli however, is the phosphorylation and subsequent degradation of I&kgr;B. I&kgr;B is phosphorylated on two N-terminal serines by the recently identified I&kgr;B kinases (IKK-&agr; and IKK-&bgr;). Site-directed mutagenesis studies indicate that these phosphorylations are critical for the subsequent activation of NF-&kgr;B in that once phosphorylated the protein is flagged for degradation via the ubiquitin-proteasome pathway. Free from I&kgr;B, the active NF-&kgr;B complexes are able to translocate to the nucleus where they bind in a selective manner to preferred gene-specific enhancer sequences. Included in the genes regulated by NF-&kgr;B are a number of cytokines, cell adhesion molecules, and acute phase proteins.
It is well-known that NF-&kgr;B plays a key role in the regulated expression of a large number of pro-inflammatory mediators including cytokines such as IL-6 and IL-8. Cell adhesion molecules, such as ICAM and VCAM, and inducible nitric oxide synthase (iNOS). Such mediators are known to play a role in the recruitment of leukocytes at sites of inflammation and in the case of iNOS, may lead to organ destruction in some inflammatory and autoimmune diseases.
The importance of NF-&kgr;B in inflammatory disorders is further strengthened by studies of airway inflammation including asthma, in which NF-&kgr;B has been shown to be activated. This activation may underlie the increased cytokine production and leukocyte infiltration characteristic of these disorders. In addition, inhaled steroids are known to reduce airway hyperresponsiveness and suppress the inflammatory response in asthmatic airways. In light of the recent findings with regard to glucocorticoid inhibition of NF&kgr;B, one may speculate that these effects are mediated through an inhibition of NF&kgr;B.
Further evidence for a role of NF-&kgr;B in inflammatory disorders comes from studies of rheumatoid synovium. Although NF-&kgr;B is normally present as an inactive cytoplasmic complex, recent immunohistochemical studies have indicated that NF-&kgr;B is present in the nuclei, and hence active, in the cells comprising rheumatoid synovium. Furthermore, NF-&kgr;B has been shown to be activated in human synovial cells in response to stimulation with TNF-&agr;. Such a distribution may be the underlying mechanism for the increased cytokine and eicosanoid production characteristic of this tissue. See Roshak, A. K., et al.,
J. Biol. Chem
., 271, 31496-31501 (1996).
The NF-&kgr;B/Rel and I&kgr;B proteins are also likely to play a key role in neoplastic transformation. Family members are associated with cell transformation in vitro and in vivo as a result of overexpression, gene amplification, gene rearrangements or translocations. In addition, rearrangement and/or amplification of the genes encoding these proteins are seen in 20-25% of certain human lymphoid tumors. In addition, a role for NF-&kgr;B in the regulation of apoptosis has been reported stregthening the role of this transcription factor in the control of cell proliferation.
Several NF-&kgr;B inhibitors are described in C. Wahl, et al.
J. Clin. Invest
. 101(5), 1163-1174 (1998), R. W. Sullivan, et al.
J. Med. Chem
. 41, 413-419 (1998), J. W. Pierce, et al.
J. Biol. Chem
. 272, 21096-21103 (1997)
The marine natural product hymenialdisine is known to inhibit NF-&kgr;B. Roshak, A., et al.,
JPET
, 283, 955-961 (1997). Breton, J. J and Chabot-Fletcher, M. C.,
JPET
, 282, 459-466 (1997).
Salicylanilides are known compounds. A general solution preparation of salicyanilides is described by M. T. Clark, R. A. Coburn. R. T. Evans, R. J. Genco,
J. Med. Chem
., 1986, 29, 25-29.
We have now discovered a novel method of inhibiting, the activation transcription factor NF-&kgr;B using salicylanilides.
SUMMARY OF THE INVENTION
An object of the present invention is to provide a method for treating diseases which may be therapeutically modified by altering the activity of transcription factor NF-&kgr;B.
Accordingly, in the first aspect, this invention provides a pharmaceutical composition comprising a compound according to Formula I.
In still another aspect, this invention provides a method of treating diseases in which the disease pathology may be therapeutically modified by inhibiting NF&kgr;B.
In a particular aspect, this invention provides methods for treating a variety of diseases associated with NF-&kgr;B activation including inflammatory disorders; particularly rheumatoid arthritis, inflammatory bowel disease, and asthma; dermatosis, including psoriasis and atopic dermatitis; autoimmune diseases; tissue and organ rejection; Alzheimer's disease; stroke; atherosclerosis; restenosis; cancer, including Hodgkins disease; and certain viral infections, including AIDS; osteoarthritis; osteoporosis; and Ataxia Telangiestasia.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a method of treatment of diseases associated with NF-&kgr;B activation, comprising administering to an animal, particularly a mammal, most particularly a human in need thereof a compound of Formula I:
wherein:
R
A
substitutes ring A 0-3 times and is independently selected from the group consisting of: NO
2
, halogen,C
1-6
alkyl, trifluoromethyl. O-C
1-6
alkyl and S-C
1-6
alkyl; and
R
B
substitutes ring B 0-3 times and is independently selected from the group consisting of: halogen,C(O)C
1-6
alky
Callahan James F.
Chabot-Fletcher Marie C.
Hui San-ming
Kinzig Charles M.
McCarthy Mary E.
Simon Soma G.
SmithKline Beecham Corporation
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