Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Patent
1990-11-16
1993-03-23
Killos, Paul J.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
560 55, 562465, 514532, G07C 6702
Patent
active
051965704
DESCRIPTION:
BRIEF SUMMARY
The invention relates to new leukotriene-B.sub.4 derivatives, the process for their production as well as their use as pharmaceutical agents.
Leukotriene-B.sub.4 (LTB.sub.4) was discovered in 1979 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. ##STR2##
The nomenclature of the leukotrienes can be gathered from the following works:
a) B. Samuelsson et al., Prostaglandins 19, 645 (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 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 that LTB.sub.4 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 was 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 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 casually 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 are involved especially in arthritis, chronic lung disease (e.g., asthma), rhinitis and inflammatory intestinal diseases.
Antagonists against LTB.sub.4 itself or inhibitors of those enzymes, which are involved in the synthesis of the LTB.sub.4, can be effective as specific medications, especially against diseases which accompany inflammations and allergic reactions.
Besides the therapeutic possibilities, which can be derived from an antagonizing of LTB.sub.4 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 recently (H. Kayama, Prostaglandins 34, 797 (1988)).
The replacement of the chemically and metabolically liable cis-delta.sup.6,7 double bond of LTB.sub.4 by a 1,2-substituted phenyl ring results in the more stable 6,7-interphenylene-leukotrienes, and antagonists, agonists and partial antagonists are obtained depending on the structural change of the functional groups and depending on the tissue type. It has now been found that by the substitution of the 5-hydroxy group by a hydrogen atom and by other derivatizing of the functional groups, LTB.sub.4 analogs are obtained which greatly antagonize the action of the natural LTB.sub.4. Duration of action and selectivity of the new compounds could be further improved by lower oxidation sensitivity or the absence of a tendency toward lactonization because of the nonexistent 5-hydroxy group.
The invention relates to a new leukotriene-B.sub.4 analogs of formula I, ##STR3## in which
R.sub.1 means radical CH.sub.2 OH, CH.sub.3, CF.sub.3, or COOR.sub.4 with R.sub.4 meaning a hydrogen atom, an alkyl radi
Buchmann Bernd
Ekerdt Roland
Frohlich Wolfgang
Heindl Joseph
Skuballa Werner
Killos Paul J.
Schering Aktiengesellschaft
LandOfFree
Leukotriene-B.sub.4 derivatives, process for their production an does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Leukotriene-B.sub.4 derivatives, process for their production an, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Leukotriene-B.sub.4 derivatives, process for their production an will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-1353020