Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1997-02-18
1999-12-28
Raymond, Richard L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514213, 514221, 540490, 540510, 540512, 540513, 540523, 540552, 540573, 540593, A61K 3155, C07D24314, C07D26714, C07D28110
Patent
active
060082143
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention relates to pharmaceutically active bicyclic compounds, pharmaceutical compositions containing the compounds and methods of using the compounds. The instant compounds inhibit platelet aggregation. These compounds also inhibit the vitronectin receptor and are useful for the treatment of osteoporosis.
BACKGROUND OF THE INVENTION
Platelet aggregation is believed to be mediated primarily through the fibrinogen receptor, or GPIIb-IIIa platelet receptor complex, which is a member of a family of adhesion receptors referred to as integrins. It has been found that frequently the natural ligands of integrin receptors are proteins which contain an Arg-Gly-Asp sequence. Von Willebrand factor and fibrinogen, which are considered to be natural ligands for the GPIIb-IIIa receptor, possess an Arg-Gly-Asp (RGD in single letter amino acid code) sequence in their primary structure. Functionally, these proteins are able to bind and crosslink GPIIb-IIIa receptors on adjacent platelets and thereby effect aggregation of platelets.
Fibronectin, vitronectin and thrombospondin are RGD-containing proteins which have also been demonstrated to bind to GPIIb-IIIa. Fibronectin is found in plasma and as a structural protein in the intracellular matrix. Binding between the structural proteins and GPIIb-IIIa may function to cause platelets to adhere to damaged vessel walls.
Also, recent studies have indicated that the attachment of osteoclasts to the bone matrix is mediated through cell surface adhesion receptors called integrins. For instance, Davies, et al., J. Cell Biol. 1989, 109, 1817, disclose that the osteoclast functional antigen, which is implicated in the regulation of bone resorption, is biochemically related to the vitronectin receptor. The vitronectin receptor, or the .alpha..sub.V .beta..sub.3 integrin, is known to bind to bone matrix proteins, such as osteopontin, bone sialoprotein and thrombospondin, which contain the tri-peptide Arg-Gly-Asp (or RGD) motif. Thus, Horton, et al., Exp. Cell Res. 1991, 195, 368, disclose that RGD-containing peptides and an anti-vitronectin receptor antibody (23C6) inhibit dentine resorption and cell spreading by osteoclasts. In addition, Sato, et al., J. Cell Biol. 1990, 111, 1713 disclose that echistatin, a snake venom peptide which contains the RGD sequence, is a potent inhibitor of bone resorption in tissue culture, and inhibits attachment of osteoclasts to bone. Fisher, et al., Endocrinology 1993, 132, 1411, has further shown that echistatin inhibits bone resorption in vivo in the rat. EP 528 587 and 528 586 report substituted phenyl derivatives which inhibit osteoclast mediated bone resorption.
The present invention discloses novel bicyclic compounds, including benzazepines and benzodiazepines, which are inhibitors of the GPIIb-IIIa receptor and inhibit platelet aggregation. Also, the instant compounds are inhibitors of the vitronectin receptor. These agents inhibit bone resorption and are useful for the treatment of osteoporosis.
SUMMARY OF THE INVENTION
In one aspect this invention is a bicyclic compound comprising a substituted six-membered ring fused to a substituted seven-membered ring as described hereinafter in formula (I).
This invention is also a pharmaceutical composition which comprises a compound of formula (I) and a pharmaceutically acceptable carrier.
This invention is further a method for inhibiting platelet aggregation in a mammal in need thereof, which comprises internally administering an effective amount of a compound of formula (I).
In another aspect, this invention provides a method for inhibiting reocclusion of an artery or vein in a mammal following fibrinolytic therapy, which comprises internally administering an effective amount of a fibrinolytic agent and a compound of formula (I). This invention is also a method for treating stroke, transient ischemia attacks, or myocardial infarction.
This invention is also a method of treating diseases which are mediated by ligands which bind to the vitronectin receptor. In a particu
REFERENCES:
patent: 5158947 (1992-10-01), Tatsuoka et al.
patent: 5693636 (1997-12-01), Bondinell et al.
Kwon Chet
Miller William Henry
Kessinger Ann M.
Kinzig Charles M.
McCarthy Mary E.
Raymond Richard L.
SmithKline Beecham Corporation
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