Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
2001-02-20
2002-07-02
Reamer, James H (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
Reexamination Certificate
active
06414025
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to inhibitors of the nuclear transcription factor kappaB (NF-&kgr;B) and to their use in therapy. Specifically, the present invention relates to the use of 2-hydroxy-4-trifluoromethylbenzoic acid derivatives to inhibit the activation of the transcription factor NF-&kgr;B.
DESCRIPTION OF PRIOR ART
The control of the expression of proteins plays a key role both in the maintenance of the normal function of cells and hence of organisms, as well as in the development of pathological processes. This control is effected through the so-called transcription factors. One of these factors is the group of proteins known as nuclear transcription factor NF-&kgr;B, formed by a family of intimately related dimeric complexes. NF-&kgr;B exists in an inactive form in the cytoplasm of many types of cells. In response to a stimulus, it becomes activated and is then translocated to the nucleus, where it binds to DNA and regulates the transcription of various genes. The activation of NF-&kgr;B can be induced by several agents such as inflammatory cytokines (for example, tumor necrosis factor-alfa (TNF-&agr;) and interleukin-1beta (IL-1&bgr;)), mitogens, bacterial lipopolysaccharides (LPS), viruses, oxidants (for example, H
2
O
2
and ozone), phorbol esters and ultraviolet light. Among the various genes whose expression is regulated by NF-&kgr;B, many genes involved in immune and inflammatory responses are included. Thus, among others, NF-&kgr;B regulates the expression of proinflammatory cytokines such as IL-1&bgr;, interleukin-2 (IL-2), interleukin-6 (IL-6), TNF-&agr; and granulocyte-macrophage colony stimulating factor (GM-CSF); chemokines such as interleukin-8 (IL-8), RANTES, macrophage inflammatory protein-1&agr; (MlP-1&agr;), monocyte chemotactic protein-1 (MCP-1) and eotaxin; inflammatory enzymes such as inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), 5-lipoxygenase (5-LO) and cytosolic phospholipase A
2
(cPLA
2
); adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and E-selectin; and receptors such as the interleukin-2 receptor and the T-cell receptor (P. J. Barnes and I. M. Adcock,
Trends Pharmacol. Sci.
1997, 18, 46-50).
Dysfunctions in the activation of NF-&kgr;B and its dependent genes have been associated with several pathologies such as acute inflammation, septic shock, transplant rejection, radiation damage, ischemia and reperfusion damage and neurodegenerative diseases (P. A. Baeuerle and T. Henkel,
Annu. Rev. Immunol.
1994, 12, 141-179), asthma and other chronic inflammatory diseases (P. J. Barnes and I. M. Adcock,
Trends Pharmacol. Sci.
1997, 18, 46-50), osteoporosis (Y. Abu-Amer and M. Mehrad Tondravi,
Nature Med.
1997, 3(11), 1189-1190), and cancer (M. A. Sovak et al.,
J. Clin. Invest.
1997, 100 (12), 2952-2960). Moreover, elevated levels of NF-&kgr;B have been detected in synovial tissue of patients with rheumatoid arthritis (H. Asahara et al.,
Biochem. Mol Biol. Int.,
1995, 37(5), 827-32), in central nervous system samples of multiple sclerosis patients (D. Gveric et al.,
J. Neuropathol. Exp. Neurol.
1998, 57(2), 168-78) and in samples of atherosclerotic tissue (K. Brand et al.,
J. Clin. Invest.
1996, 97(7), 1715-22), and it has been described that amyloid &bgr; peptide, which accumulates in plaques of Alzheimer patients, activates NF-&kgr;B in central nervous system cells (C. Behl et al.,
Cell
1994, 77, 817-827). A high increase in the nuclear translocation of NF-&kgr;B has also been observed in dopaminergic neurons of patients with Parkinson's disease (S. Hunot et al.,
Proc. Natl. Acad. Sci. USA
1997, 94(14), 7531-7536). Furthermore, NF-&kgr;B has also been reported to be involved in the transcriptional activation of viruses such as human immunodeficiency virus (HIV), cytomegaloviruses, adenoviruses and herpesviruses.
On the other hand, it has been shown that the cytokines, inflammatory enzymes, adhesion molecules and other proteins whose expression is regulated by NF-&kgr;B play an important role in a broad range of disorders such as inflammation; asthma; adult respiratory distress syndrome (ARDS); immunoinflammatory and autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, psoriasis, inflammatory bowel disease, lupus and glomerulonephritis; arthrosis; septic shock; atherosclerosis; cancer; osteoporosis; preterm labour; transplant rejection; neurodegenerative diseases such as dementia, including Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis; and viral infections.
In view of the above, the agents which are able to modulate the activity of the transcription factor NF-&kgr;B and/or the expression of genes which are dependent on this transcription factor could be of great utility as therapeutic agents for the treatment or prevention of the above-mentioned disorders. It is thus of great interest to find agents which are capable of regulating NF-&kgr;B activity.
2-Acetyloxy-4-trifluoromethylbenzoic acid, better known by its International Nonproprietary Name (INN) triflusal, is a platelet aggregation inhibitor marketed for the treatment of thromboembolic diseases under the trademark Disgren®. Its main metabolite, 2-hydroxy-4-trifluoromethylbenzoic acid (also known by the acronym HTB), also possesses a remarkable activity as platelet antiaggregant. Both compounds are described in U.S. Pat. No. 4,096,252.
The present inventors have found that, surprisingly, both triflusal and its metabolite, HTB, inhibit NF-&kgr;B activation. Moreover, it has been found that both compounds are potent inhibitors of the expression of genes that are transcriptionally regulated by NF-&kgr;B. Due to this new activity now discovered, triflusal and HTB are potentially useful in the treatment or prevention of disorders where the activation of NF-&kgr;B and its dependent genes is involved, such as those mentioned above.
DESCRIPTION OF THE INVENTION
The present invention is based upon the finding that triflusal and its metabolite, HTB, are potent inhibitors of the activation of the transcription factor NF-&kgr;B. As mentioned above, NF-&kgr;B is an ubiquitous transcription factor that acts by binding to DNA, activating in this manner the expression of various genes, many of them involved in the immune and inflammatory response. The present invention shows that triflusal and HTB inhibit the activation of NF-&kgr;B induced by various agents such as TNF-&agr;, immune complexes and LPS in several types of cells, such as human umbilical vein endothelial cells (HUVEC), macrophages and monocytes. Moreover, it is also shown that triflusal and HTB inhibit the expression of several proteins in whose transcriptional regulation NF-&kgr;B is involved, such as for example VCAM-1, iNOS, COX-2, MCP-1 and TNF-&agr;. Therefore, triflusal and HTB are useful as therapeutic or preventive agents in those pathological situations where NF-&kgr;B and/or the proteins whose expression is regulated by this transcription factor are involved.
Triflusal and HTB can be generically represented by means of formula I:
wherein R represents hydrogen (HTB) or COCH
3
(triflusal).
It is an object of the present invention to provide the use of a compound of formula I for the manufacture of a medicament useful for inhibiting the activation of the transcription factor NF-&kgr;B. The use of a pharmaceutically acceptable salt of a compound of formula I or of a prodrug thereof are also encompassed within the scope of the present invention.
Another object of the present invention is to provide the use of a compound of formula I or a pharmaceutically acceptable salt or a prodrug thereof for the manufacture of a medicament useful for inhibiting the expression of genes which are dependent on and/or regulated by, at least partially, the transcription factor NF-&kgr;B. In a preferred embodiment, the gene encodes IL-1&bgr;, IL-2, IL-6, TNF-&agr;, GM-CSF, IL-8, RANTES, MIP-1&agr;, MCP-1, eotaxin, iNOS, COX-2, 5-LO, cPLA
2
, ICAM-1, VCAM-1, E-selectin
Acosta Agustí Miralles
Cavalcanti De Maria Fernando
Crespo Mariano Sanchez
Dalmau Javier Forn
De Arriba Alberto Fernandez
J. Uriach & Cia S.A.
Reamer James H
Rothwell Figg Ernst & Manbeck
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