Compounds that inhibit complement and/or suppress immune activit

Details Compounds that inhibit complement and/or suppress immune activit Compounds that inhibit complement and/or suppress immune activit

1994-01-21

1996-04-09

Ivy, C. Warren

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

514382, 514462, 548237, 548252, 549236, 549264, 549345, A61K 3142, A61K 3141, C07D30794

Patent

active

055062474

DESCRIPTION:

BRIEF SUMMARY
1. FIELD OF THE INVENTION

The present invention relates to compounds which inhibit complement and/or possess immunosuppressive activity. In particular, the compounds of the present invention, and the pharmaceutically acceptable salts thereof, selectively inhibit complement at the C5 step of complement activation. The compounds of the invention are substituted dihydrobenzofurans, spirobenzofuran-2(3H)-cycloalkanes, and their open chain intermediates that exhibit such inhibitory activates. Compounds of the invention also include 6,7-disubstituted spirobenzofuran-2(3H)-cycloalkanes and 4-substituted spirobenzofuran-2(3H)-cycloalkanes. The invention relates to the use of these compounds for therapy of immune and/or inflammatory disorders.


2. BACKGROUND OF THE INVENTION



2.1 The Complement System

The complement system is a group of proteins that constitutes about 10 percent of the globulins in the normal serum of humans (Hood, L.E. et al. 1984, Immunology, 2d Edition, The Benjamin/Cummings Publishing Co., Menlo Park, Calif., p. 339). Complement (C) plays an important role in the mediation of immune and allergic reactions (Rapp, H. J. and Borsos, T., 1970, Molecular Basis of Complement Action, Appleton-Century-Crofts (Meredith), New York). The activation of C components leads to the generation of a group of factors, including chemotactic peptides that mediate the inflammation associated with complement-dependent diseases. The sequential activation of the complement cascade may occur via the classical pathway involving antigen-antibody complexes, or by an alternative pathway which involves the recognition of certain cell wall polysaccharides. The activities mediated by activated complement proteins include lysis of target cells, chemotaxis, opsonization, stimulation of vascular and other smooth muscle cells, degranulation of mast cells, increased permeability of small blood vessels, directed migration of leukocytes, and activation of B lymphocytes, macrophages and neutrophils (Eisen, H.N., 1974, Immunology, Harper & Row, Publishers, Inc., Hagerstown, Md., p. 512).
During proteolytic cascade steps, biologically active peptide fragments, the anaphylatoxins C3a, C4a, and C5a (See WHO Scientific Group, WHO Tech. Rep. Ser. 1977, 606, 5 and references cited therein), are released fromthe third (C3), fourth (C4), and fifth (C5) native complement components (Hugli, T. E. CRC Crit. Rev. Immunol. 1981, 1, 321; Bult, H. and Herman, A. G. Agents Actions 1983, 13, 405). The C5a fragment, a cationic peptide derived from the first 74 amino acids of the amino-terminus of the C5 alpha subunit (Tack, B.F. et al. Biochemistry 1979, 18, 1490), is of particular pathological relevance. Regulation of C5a activity is by the endogenous plasma enzyme carboxypeptidase N (E.C. 3.4.12.7), which rapidly removes the carboxy-terminal arginine from C5a, producing the less potent but still active C5a des Arg. Reported effects of C3a and C5a upon specific immune responses are listed in Table I.


TABLE I ______________________________________ EFFECTS OF COMPLEMENT COMPONENTS C3a AND C5a ON SPECIFIC IMMUNE RESPONSES Immune Response C3a C5a/C5a des Arg ______________________________________ Specific antibody production Suppression Enhancement in response to sheep red blood cells Polyclonal antibody Suppression Enhancement production in response to Fc antibody fragment T cell proliferation Suppression Enhancement in response to tetanous toxoid T cell proliferation in No effect Enhancement mixed lymphocyte reaction T cell-mediated cytotoxicity Suppression Enhancement ______________________________________ contraction of smooth muscle (Wissler, J. H. Eur. J. Immunol. 1972, 2, 73), degranulation of mast cells (Johnson, A. R. et al., Immunol. 1975, 28, 1067), secretion of azurophilic granular enzymes from polymorphonuclear neutrophils (PMN) (Webster, R. O. et al., Immunopharmacol. 1980, 2, 201), and the chemotaxis of PMN (Wissler, J. H. Eur. J. Immunol. 1972, 2, 73; Becker, E. L. Trends Pha

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