Leukotriene-B.sub.4 derivatives, process for their production an

Details Leukotriene-B.sub.4 derivatives, process for their production an Leukotriene-B.sub.4 derivatives, process for their production an

1994-05-27

1996-03-26

Ivy, C. Warren

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

514572, 549295, 562505, 562508, 562512, 560190, 560201, A61K 3134, A61K 3119

Patent

active

055020755

DESCRIPTION:

BRIEF SUMMARY
The invention relates to new leukotriene-B.sub.4 derivatives, process for their production as well as their use as pharmaceutical agents. The new compounds are structural analogs of previously known leukotriene-B.sub.4 antagonists, that contain a six-membered ring as a basic structural element (DE-A 39 17 597). Leukotriene B.sub.4 (LTB.sub.4) was discovered by B. Samuelsson et al. as a metabolite of 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.
KEY: ##STR2##
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 et al., Science 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.
It is known from the 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. Further, because of its chemotactic activity, it indirectly changes the vascular permeability, and a synergism with prostaglandin E.sub.2 is observed. LTB.sub.4 obviously plays a decisive role in inflammatory, allergic and immunological processes.
Leukatrienes and especially LTB.sub.4 are involved in skin diseases, which accompany inflammatory processes (increased vessel 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. Further, leukotrienes and LTB.sub.4 especially are involved in arthritis, chronic lung diseases (e.g., asthma), rhinitis and inflammatory intestinal diseases as well as reperfusion damages of various organs.
Antagonists against LTB.sub.4 receptors or inhibitors of those enzymes which are involved in the synthesis of the LTB.sub.4 should be effective as specific medications, especially against diseases which accompany inflammations and allergic reactions.
Besides therapeutic possibilities, which can be derived from counteracting of LTB.sub.4 action with LTB.sub.4 analogs, the usefulness and potential use of leukotriene-B.sub.4 agonists for the treatment of fungus diseases of the skin was also able to be shown (H. Katayama, Prostaglandins 34, 797 (1988)).
The invention relates to leukotriene-B.sub.4 derivatives of formula I ##STR3## in which R.sup.1 means CH.sub.2 OH, CH.sub.3, CF.sub.3, COOR.sup.5 CONR.sup.6 R.sup.7, or radical with 1-15 C atoms, or several times, C.sub.3 -C.sub.10 cycloalkyl, C.sub.6 -C.sub.10 aryl radical optionally substituted, independent from one another, once or several times by halogen, phenyl, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, fluoromethyl, chloromethyl, trifluoromethyl, carboxyl or hydroxy, or a 5-6 membered aromatic heterocyclic ring with at least 1 heteroatom, cycloalkyl, C.sub.6 -C.sub.10 aryl radical optionally substituted by 1-3 halogen, phenyl, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, fluoromethyl, chloromethyl, trifluoromethyl, carboxyl or hydroxy, CH.sub.2 --CO--(C.sub.6 -C.sub.10) aryl or a 5-6 membered ring with at least 1 heteroatom, --CH.dbd.CH-- or a tetramethylene group, group,

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