Platelet-activating factor (PAF) has recently been identified as an acetyl glyceryl ether phosphorylcholine (AGEPC), i.e., 1-O-hexadecyl/octadecyl-2-O-acetyl-sn-glyceryl-3-phosphorylcholine (Hanahan, D. S. et al., J. Biol. Chem., 255: 5514, 1980). Even before its chemical identification, PAF has been linked to various biologic activities and pathways making it one of the important mediators responsible for a variety of physiological processes including activation or coagulation of platelets, pathogenesis of immune complex deposition, smooth muscle contraction, inflammation as well as respiratory, cardiovascular and intravascular alterations. These physiological processes are known to be associated with a large group of diseases, for example, inflammatory diseases, cardiovascular disorders, asthma, lung edema, and adult respiratory distress syndrome. It is therefore only natural that more and more scientific investigators are focusing their work on the search of a PAF-antagonist or inhibitor for the treatment and/or the prevention of these common diseases.
The compounds of the present invention are potent and specific PAF-antagonists. They include various substituted 1-benzylidene-indene derivatives of Structure (I) especially where R.sup.2 is an amino sulfonyl group. ##STR1##
These indene derivatives are related to sulindac, a non-steroidal anti-inflammatory drug disclosed by U.S. Pat. Nos. 3,654,349; 3,870,753 and 3,994,600. However, these patents do not disclose the indene derivatives as PAF antagonists nor do they describe the 1-(p-aminosulfonylbenzylidine)-derivatives of the present invention.
Accordingly, it is the object of the present invention to provide novel derivatives of Structure (I) as specific PAF-antagonists.
Another object of this invention is to provide processes for the preparation of novel derivatives of Structure (I).
A further object of this invention is to provide a pharmaceutically acceptable composition containing at least one of the compounds of Structure (I) as the active ingredient for the treatment of diseases which are subject to the mediation of a PAF-antagonist.
Still a further object of this invention is to provide a method of treatment comprising the administration of a therapeutically sufficient amount of at least one of the compounds of Structure (I) to a patient suffering from various skeletal-muscular disorders including but not limited to inflammation, e.g., osteoarthritis, rheumatoid arthritis and gout, hypertension; cardiovascular disorder; asthma; bronchitis; lung edema; or adult respiratory distress syndrome.