Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Patent
2000-03-27
2000-12-12
Gerstl, Robert
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
514567, 560 35, 562440, C07C40500, A01K 315575
Patent
active
061600121
DESCRIPTION:
BRIEF SUMMARY
The invention relates to new leukotriene-B.sub.4 derivatives, process for their production and their use as pharmaceutical agents. The new compounds are optically active structural analogues of previously known leukotriene-B.sub.4 antagonists, which contain a six-membered ring as a basic structural element (DE-A 39 17 597, DE-A 42 27 790.6, DE 42 42 390). ##STR2## KEY: Arachidonsaure=arachidonic acid
Leukotriene B.sub.4 (LTB.sub.4) was discovered by B. Samuelsson et al. as a metabolite of the arachidonic acid. In the biosynthesis, leukotriene A.sub.4 is formed by the enzyme 5-lipoxygenase first as a central intermediate product, which then is converted by a specific hydrolase into the LTB.sub.4.
The nomenclature of the leukotrienes can be deduced from the following works:
a) B. Samuelsson et al., Prostaglandins 19, 654 (1980); 17, 785 (1979).
b) C. N. Serhan et al., Prostaglandins 34, 201 (1987).
The physiological and especially the pathophysiological importance of leukotriene B.sub.4 is summarized in several more recent works: a) The Leukotrienes, Chemistry and Biology eds. L. W. Chakrin, D. M. Bailey, Academic Press 1984. b) J. W. Gillard et al., Drugs of the Future 12, 453 (1987). c) B. Samuelsson, Sciences 237, 1171 (1987). d) C. W. Parker, Drug Development Research 10, 277 (1987). e) W. R. Henderson, Annals of Internal Medicine 121, 684 (1994). It follows from the above that LTB.sub.4 is an important inflammation mediator for inflammatory diseases, in which leukocytes invade the affected tissue.
The effects of LTB.sub.4 are triggered on the cellular plane by the binding of LTB.sub.4 to a specific receptor.
It is known concerning LTB.sub.4 that it causes the adhesion of leukocytes to the blood vessel wall. LTB.sub.4 is chemotactically active, i.e., it triggers a directed migration of leukocytes in the direction of a gradient of increasing concentration. Furthermore, it indirectly changes the vascular permeability based on its chemotactic activity, whereby a synergism with prostaglandin E.sub.2 is observed. LTB.sub.4 obviously plays a decisive role in inflammatory, allergic and immunological processes.
Leukotrienes and especially LTB.sub.4 are involved in skin diseases, which are accompanied by inflammatory processes (increased vascular permeability and formation of edemas, cell infiltration), increased proliferation of skin cells and itching, such as, for example, in eczemas, erythemas, psoriasis, pruritus and acne. Pathologically increased leukotriene concentrations are involved either causally in the development of many dermatitides or there is a connection between the persistence of the dermatitides and the leukotrienes. Clearly increased leukotriene concentrations were measured, for example, in the skin of patients with psoriasis, atopic dermatitis, allergic contact dermatitis, bullous pemiphigoids, delayed duchurticaria and allergic vasculitis.
Leukotrienes and especially LTB.sub.4 are also involved in the diseases of internal organs, for which an acute or chronic inflammatory component was described, e.g.: joint diseases (rheumatic arthritis); diseases of the respiratory tract (asthma and chronically obstructive lung diseases (OPD)); inflammatory intestinal diseases (ulcerous colitis and Crohn's disease); as well as reperfusion damages (to the heart, intestinal or renal tissues), which result by the temporary pathological obstruction of blood vessels, such as glomerulonephritis, NSAID gastropathies, multiple sclerosis, rhinitis and inflammatory eye diseases.
Further, leukotrienes and especially LTB.sub.4 are involved in the disease of multiple sclerosis and in the clinical appearance of shock (triggered by infections, burns or in complications in kidney dialysis or other separately discussed perfusion techniques).
In addition, leukotrienes and especially LTB.sub.4 have an effect on the formation of white blood cells in the bone marrow, on the growth of unstriped muscle cells, of keratinocytes and of B-lymphocytes. LTB.sub.4 is therefore involved in diseases with inflammatory processes and in dise
Buchmann Bernd
Frohlich Wolfgang
Giesen Claudia
Hennekes Hartwig
Jaroch Stefan
Gerstl Robert
Schering Aktiengesellschaft
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