Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1999-07-27
2000-12-12
Ramsuer, Robert W.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
540512, A61K 315513, A61P 702, C07D40112
Patent
active
061599646
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention relates to pharmaceutically active compounds which inhibit the vitronectin receptor and are useful for the treatment of diseases wherein ihibition of the vitronectin receptor is indicated, such as inflammation, cancer, angiogenesis, atherosclerosis, restenosis, and diseases wherein bone resportion is a factor.
BACKGROUND OF THE INVENTION
Integrins are a superfamily of cell adhesion receptors, which are transmembrane glycoproteins expressed on a variety of cells. These cell surface adhesion receptors include gpIIb/IIIa, the fibrinogen receptor, and .alpha..sub.v .beta..sub.3, the vitronectin receptor. The fibrinogen receptor gpIIb/IIIa is expressed on the platelet surface and it mediates platelet aggregation and the formation of a hemostatic clot at the site of a bleeding wound. Philips, et al., Blood., 1988, 71, 831.
The vitronectin receptor .alpha..sub.v .beta..sub.3 is expressed on a number of cells, including endothelial, smooth muscle, osteoclast, and tumor cells, and, thus, it has a variety of functions. The .alpha..sub.v .beta..sub.3 receptor expressed on the membrane of osteoclast cells is believed to play a role in the bone resportion process and contribute to the development of osteoporosis. Ross, et al., J. Biol. Chem., 1987, 262, 7703; Fisher, et al., Endochrinology 1993, 132, 1411; Bertolini et al., J. Bone Min. Res., 6, Sup. 1, S146 252; EP 528 587 and 528 586. The .alpha..sub.v .beta..sub.3 receptor expressed on human aortic smooth muscle cells stimulates their migration into neointima, which leads to the formation of atherosclerosis and restenosis after angioplasty. Brown, et al., Cardiovascular Res., 1994, 28, 1815. Additionally, a recent study has shown that a .alpha..sub.v .beta..sub.3 antagonist is able to promote tumor regression by inducing apoptosis of angiogenic blood vessels. Brooks, et al., Cell, 1994, 79, 1157. Thus, agents that would block the vitronectin receptor would be useful in treating diseases mediated by this receptor, such as osteoporosis, atherosclerosis, restenosis and cancer.
Alig et al., EP 0 381 033, Hartman, et al., EP 0 540,334, Blackburn, et al., WO 93/08174, Bondinell, et al., WO 95/18619, Bondinell, et al., WO 94/14776, Blackburn, et al. WO 95/04057, Egbertson, et al, EP 0 478 328, Sugihara, et al. EP 529,858, Porter, et al., EP 0 542 363, and Fisher, et al., EP 0 635 492, and many others disclose certain compounds that are useful for selectively inhibiting the fibrinogen receptor. PCT/US95/08306, filed Jun. 29, 1995 (SmithKline Beecham Corp.) and PCT/US95/08146 filed Jun. 29, 19951995 (SmithKline Beecham Corp.) disclose vitronectin receptor selective antagonists. However, there are few reports of compounds which are potentvitronectin receptor antagonists. It has now been discovered that certain appropriately substituted amino pyridine compounds are potent inhibitors of the vitronectin receptor. In particular, it has been discovered that the amino pyridine moiety may be combined with a fibrinogen atagonist template to prepare compounds which are more potent inhibitors of the vitronectin receptor than the fibrinogen receptor.
SUMMARY OF THE INVENTION
This invention comprises compounds of the formula (I) as described hereinafter, which have pharmacological activity for the inhibition of the vitronection receptor and are useful in the treatment of inflammation, cancer, cardiovascular disorders, such as atherosclerosis and restenosis, and diseases wherein bone resorption is a factor, such as osteoporosis.
This invention is also a pharmaceutical composition comprising a compound according to formula (I) and a pharmaceutically acceptable carrier.
This invention is also a method of treating diseases which are mediated by the vitronectin receptor. In a particular aspect, the compounds of this invention are useful for treating atherosclerosis, restenosis, inflammation, cancer and osteoporosis.
DETAILED DESCRIPTION
This invention comprises novel compounds which are more potent inhibitors of the vitronectin receptor than the
REFERENCES:
patent: 3450707 (1969-06-01), Bailey
patent: 3627754 (1971-12-01), Ning et al.
Ali Fadia E.
Bondinell William E.
Keenan Richard M.
Ku Thomas Wen-Fu
Miller William H.
Kinzig Charles M.
McCarthy Mary E.
Ramsuer Robert W.
SmithKline Beecham Corporation
Venetianer Stephen
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