Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Patent
1995-10-06
1997-04-01
Prior, Kimberly J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
514174, 514176, 514177, 514178, 514179, 514180, 514181, 540 63, 540 70, 540110, 552564, 552565, 552566, 552570, 552572, 552573, 552574, 552576, 552577, 552588, A61K 3157, C07J 500
Patent
active
056165730
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/EP94/00937 filed Mar. 24, 1994.
The invention relates to glucocorticoids of general formula I
O-GC is the radical of a 21-hydroxycorticoid that has an antiinflammatory action,
Val represents a valine radical in the 21-position of the corticoid, and
R means a hydrogen atom or a hydrocarbon radical with up to 32 carbon atoms that is optionally substituted by hydroxy groups, amino groups, oxo groups and/or halogen atoms and/or interrupted by oxygen atoms, SO.sub.2 groups and/or NH groups and their salts.
The glucocorticoids according to the invention are valuable intermediate products and/or pharmacologically effective substances which are used, i.a., for the treatment of inflammatory conditions that are characterized by increased activity of the enzyme leukocyte-elastase.
Glucocorticoids are the best-known class of antiinflammatory active ingredients. Owing to their broad range of uses and their great antiinflammatory action, corticoid preparations are therapeutic agents of first choice in a wide variety of inflammatory diseases, such as, for example, diseases of the rheumatoid group, allergies, inflammatory diseases of the lungs, heart, and intestines, bronchial asthma, hyperproliferative diseases of the skin (psoriasis), eczemas, auto-immune diseases, or states of shock.
Their potential side effects, such as suppression of the brain-pituitary gland-suprarenal axis, their catabolic action, their influence on salt and water balance, osteoporosis, their influence on the blood-sugar level in the case of diabetics or the induction of skin atrophy in the case of topical application keep this class of substances from being put to an even broader range of therapeutic uses. According to present knowledge, these side effects, just like the antiinflammatory action of the glucocorticoids, are mediated by the same receptor. Up to now, therefore, reductions of the side-effect potential have been achieved by increasing the metabolic clearance of local-action corticoids (anti-drug principle). More lipophilic prodrugs are supposed to promote the penetration of corticoids into the skin and improve the retention of corticoids in the lungs. Despite the reduced side-effect potential of modern corticoids, especially long-term treatment with active ingredients of this class of substances remains critical.
Leukocyte-elastase is a serine-protease with a molecular weight of about 30,000 D. It is formed in promyelocytes and is found mainly in neutrophilic granulocytes [Duswald, K. H. (1983), Zur Pathobiochemie der Leukozyten-Elastase [Pathobiochemistry of Leukocyte-Elastase], GIT Verlag Ernst Giebler, Darmstadt.] Their occurrence is also described in Monozyten, Lymphozyten und eosinophilen Granulozyten [Monocytes, Lymphocytes and Eosinophilic Granulocytes] [Kargi et al. (1990)]. Elastase and Cathepsin G of Human Monocytes: Heterogeneity and Subcellular Localization to Peroxidase-Positive Granules. The Journal of Histochemistry and Cytochemistry 38: 1179-1186; Lungarella et al. (1992). Identification of Elastase in Human Eosinophils: Immunocalization, Isolation and Partial Characterization. Archives of Biochemistry and Biophysics, 292: 128-135; Bristow et al. (1991). Elastase is a constituent product of T cells. Biochemical and Biophysical Research Communications, 181: 232-239.] The enzyme is secreted in vitro after stimulation of granulocytes and monocytes [Schmidt (1978). Differential Release of Elastase and Chymotrypsin from Polymorphonuclear Leukocytes. In: Neutral Proteases of Human Polymorphonuclear Leukocytes. Havemann and Janoff (Editors) Urban & Schistzenberg, Inc. Baltimore, Munich; Xie et al. (1993). Release of Elastase from Monocytes Adherent to a Fibronectin-Gelatin Surface. Blood 81: 186-192.] High elastase activities are observed in vivo in the case of inflammatory diseases of the lungs, in the case of rhinitis, in synovial fluid in the case of rheumatoid arthritis, and on the skin surface in the case of different forms of eczema [Tanaka et al. (1990). A Sensitive and Specific Assay for
Brumby Thomas
Esperling Peter
Laurent Henry
Topert Michael
Zentel Hans J.
Prior Kimberly J.
Schering Aktiengesellschaft
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