Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1996-02-05
1998-07-07
Ford, John M.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514473, 549 63, 549321, C07D30733, A61K 31335, A61K 3138
Patent
active
057769745
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
1. Field of the Invention
This application is a 371 of PCT/GB94/01437 filed Jul. 1, 1994.
This invention relates to compounds for use as medicaments and to pharmaceutical compositions containing these compounds.
2. Description of Related Art
Responses by the immune system to inhaled proteins (allergens/antigens) underlie the clinical presentation of allergic rhinitis (e.g. hayfever) and asthma.
Research in Immunology has established that the cross-linking of at least two IgE antibodies (these are naturally bound by their Fc portion to receptors on the surface of human leucocytes, namely blood basophils and tissue mast cells) sets into motion a series of biochemical and pharmacological events leading to the expression of clinical allergy. The cross-linking of surface bound IgE either by allergen or mimicked by using anti-IgE antibodies results in the release of potent mediators of inflammation which are stored or are synthesized within the granules of basophils and mast cells. The major inflammation inducing substance that is released is histamine, but more than twenty other molecules have been defined following the positive signal associated with cross-linking of IgE on the surface of these cells. Overall the release of these agents results in dramatic changes in smooth muscle, in the vasculature and in release of other chemotactic factors which attract other inflammatory cells (e.g. eosinophils, neutrophils). This leads to major synergism of these compounds and amplification of the inflammatory response which then manifests as clinical allergy, e.g., difficulty in breathing, itching, excess mucous secretion, etc. up to and including life-threatening generalized allergic reaction in some rare situations.
Therapeutically, many agents are used to try to prevent the release of mediators from mast cells and basophils and/or to treat the downstream events by blocking or ameliorating the effects of the mediators on target tissues. Therapeutic agents commonly employed fall under the following main groups: histamine, i.e. the major mediator of the allergic response. to overcome indirectly the downstream effects on vasculature and smooth muscle. cells/basophil degranulation. This prophylactic must be taken continuously. It does not prevent the cross-linking of IgE but it somehow interferes with subsequent events. downstream biochemical events particularly associated with cyclic nucleotides. response. They are either administered locally and/or systematically.
None of these treatments is ideal and each has degrees of problems such as side effects and breakthroughs. Therefore, new agents are constantly being sought which may contribute to control of the allergic response prophylactically and/or therapeutically.
Immunosuppressant compounds induce an inhibition of the immune response system. Compounds which are known to exhibit immunosuppressant activity include the fungal metabolite Cyclosporin A and the macrolide antibiotic (a metabolite from Streptomyces tsukabaensis) termed FK506. Both of these agents have been used clinically and experimentally to suppress the immune system in transplantation and in the treatment of a number of diseases.
The immune mediated rejection process is the major cause of graft loss in organ transplantation. Dramatic improvements in immunosuppression (directed against proliferating T cells) and subsequent organ graft and patient survival have been obtained using Cyclosporin A. Encouraging results have also been obtained with FK506.
Autoimmune diseases are disorders where the host discrimination of "self" versus "non-self" breaks down and the individual's immune system (both acquired and innate components) attacks self tissues. These diseases range from extremely common entities such as rheumatoid arthritis, thyroid autoimmune disease and type 1 diabetes mellitus to less common entities such as multiple sclerosis and to rarer disorders such as myasthenia gravis. Advances in basic biomedical science and, in particular, in immunology have indicated that the main a
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Bycroft Barrie Walsham
Sewell Herbert Fitzgerald
Stewart Gordon Sydney Anderson Birnie
Williams Paul
Ford John M.
Sripada Pavanaram K.
The University of Nottingham
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