Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Patent
1996-11-08
1999-01-12
Shippen, Michael L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
514557, 514613, 514729, 554227, 554230, 560106, 560126, 560231, 562508, 564124, 568670, A61K 31215
Patent
active
058590544
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). 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 to the LTB.sub.4. ##STR3##
The nomenclature of the leukotrienes can be gathered from the following works:
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). 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 bond of LTB.sub.4 on a specific receptor.
It is known concerning LTB.sub.4 that it causes the adhesion of leukocytes on the blood vessel wall. LTB.sub.4 is chemotactically effective, 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, and 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 or atopic dermatitis.
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 (arthritis); diseases of the respiratory tract (asthma, rhinitis and allergies); inflammatory intestinal diseases (colitis); as well as reperfusion damages (to the heart, intestinal or renal tissues), which result by the temporary pathological obstruction of blood vessels.
Further, leukotrienes and especially LTB.sub.4 are involved in the disease of multiple sclerosis and in the clinical picture of shock (triggered by infections, burns or in complications in kidney dialysis or other separately discussed perfusion techniques).
Leukotrienes and especially LTB.sub.4 further 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 diseases with pathologically increased formation and growth of cells.
For example, leukemia or arteriosclerosis represent diseases with this clinical picture.
By the antagonizing of the effects, especially by LTB.sub.4, the active ingredients and their forms of administration of this invention are specific medicines for diseases of humans and animals, in which especially leukotrienes play a pathological role.
Besides the therapeutic possibilities, which can be derived from an antagonizing of LTB.sub.4 action with LTB.sub.4
Buchmann Bernd
Ekerdt Roland
Frohlich Wolfgang
Giesen Claudia
Heindl Josef
Schering Aktiengesellschaft
Shippen Michael L.
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