Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1994-06-28
1996-07-30
Fan, Jane
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514 58, 514445, 536103, 549 66, 5462804, A61K 3138, A61K 3144, C07D33332, C07D40906
Patent
active
055412025
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/EP92/01816 08/06/92 now WO 93/04056.
The invention relates to new leukotriene-B.sub.4 antagonists, 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.
KEY:
##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 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 to 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.
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 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 are involved especially in arthritis, chronic lung diseases (e.g., asthma), rhinitis and inflammatory intestinal diseases.
Antagonists to 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.
Compounds with a carboxybenzenephenylpropionic acid structure that have leukotriene-D.sub.4 and leukotriene-B.sub.4 antagonistic properties are already known from EP276064.
Compounds were found that surprisingly strongly antagonize the effect of the natural LTB.sub.4.
The invention relates to leukotriene-B.sub.4 antagonists of formula I, ##STR4## in which
X represents C.sub.1 -C.sub.4 -alkoxy or --S(O).sub.p --(C.sub.1 -C.sub.4)-alkyl,
p represents 0, 1 or 2
Y represents a hydrogen atom or the radical CO--A--COR with A meaning an alkylene group with 1-6 C atoms in the chain or a radical ##STR5##
R.sub.1 and R.sub.2 represent the radical OH,
--O--(C.sub.1 -C.sub.4)-alkyl, --O--(C.sub.3 -C.sub.6)-cycloalkyl, --O--(C.sub.6 -C.sub.10)-aryl, --O--(C.sub.7 -C.sub.12)-aralkyl or the radical NR.sub.3 R.sub.4 with R.sub.3 meaning hydrogen, (C.sub.1 -C.sub.4)-alkyl, (C.sub.3 -C.sub.6)-cycloalkyl or (C.sub.7 -C.sub.12)-aralkyl and R.sub.4 meaning (C.sub.1 -C.sub.4)-alkyl, (C.sub.3 -C.sub.6)-cycloalkyl or (C.sub.7 -C.sub.12)-aralkyl as well as their salts with physiologically compatible bases and their cyclodextrin clathrates.
X, R.sub.1 and R.sub.2 as C.sub.1 -C.sub.4 -alkoxy group can mean: methoxy, ethoxy, n-propoxy, isopropxy, n-butoxy, sec.-butoxy and tert.-butoxy.
The C.sub.1 -C.sub.4 -alkyl radical in the group --S(O).sub.p --(C.sub.1 -C.sub.4)-
REFERENCES:
patent: 4992576 (1991-02-01), Gapinski
patent: 4999436 (1991-03-01), Witzel et al.
patent: 5235064 (1993-08-01), Gapinski
Nobles et al. Journal of Pharmaceutical Sciences vol. 53 No. 2 1964 pp. 115-126.
Thiophene and Its Derivatives 1952 Interscience Publishers Inc. N.Y. by Blicke. Thornber Chemical Society Reviews vol. 8, No. 4, 1979. pp. 563-580 .
Buchmann Bernd
Ekerdt Roland
Frohlich Wolfgang
Giesen Claudia
Heindl Josef
Fan Jane
Schering Aktiengesellscaft
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