Bicyclic fibrinogen antagonists

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...

Patent

Rate now

  [ 0.00 ] – not rated yet Voters 0   Comments 0

Details

514213, 540504, 540512, 540513, 540514, 540523, A61K 315513, C07D24314, A61P 702

Patent

active

061178667

DESCRIPTION:

BRIEF SUMMARY
FIELD OF THE INVENTION

This invention relates to novel bicyclic compounds which inhibit platelet aggregation, pharmaceutical compositions containing the compounds and methods of using the compounds.


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.
Linear and cyclic peptides which bind to vitronectin and contain an RGD sequence are disclosed in WO 89/05150 (PCT US88/04403). EP 0 275 748 discloses linear tetra- to hexapeptides and cyclic hexa- to octapeptides which bind to the GPIIb-IIIa receptor and inhibit platelet aggregation. Other linear and cyclic peptides, the disclosure of which are incorporated herein by reference, are reported in EP-A 0 341 915. However, the peptide like structures of such inhibitors often pose problems, such as in drug delivery, metabolic stability and selectivity. Inhibitors of the fibrinogen receptor which are not constructed of natural amino acid sequences are disclosed in EP-A 0 372,486, EP-A 0 381 033 and EP-A 0 478 363. WO 92/07568 (PCT/US91/08166) discloses fibrinogen receptor antagonists which mimic a conformational .gamma.-turn in the RGD sequence by forming a monocyclic seven-membered ring structure. There remains a need, however, for novel fibrinogen receptor antagonists (e.g. inhibitors of the GPIIb-IIIa protein) which have potent in vivo and in vitro effects and lack the peptide backbone structure of amino acid sequences.
The present invention discloses novel bicyclic compounds including benzazepines and benzodiazepines, which are inhibitors of the GPIIb-IIIa receptor and inhibit platelet aggregation. Certain 5-phenyl-1,4-benzodiazepines are known as a class of drugs which affect the central nervous system, and have been used as anxiolytics. See Sternbach, L. H., J. Med. Chem., 22, 2 (1979). It has also been disclosed that certain 5-phenyl-1,4-benzodiazepines antagonize the effects of cholecystokinin. See Friedinger, Med. Res. Rev., 9, 271 (1989). Certain bicyclic compounds which have fibrinogen antagonist activity are disclosed in WO 93/08174 (PCT/US92/08788), WO 93/00095 (PCT/US/92/05463) and WO 94/14776 (PCT/US93/12436).


SUMMARY OF THE INVENTION

In one aspect this invention is a compound as hereinafter disclosed for inhibiting platelet aggregation.
This invention is also a pharmaceutical composition for inhibiting platelet aggregation or clot formation, which comprises a compound of the invention and a pharmaceutically acceptable carrier.
This invention further comprises the use of a compound as hereinafter described in the manufacture of a medicament for inhibiting platelet aggregation
In another aspect, this invention provides a method for inhibiting reocclusion of an artery or vein in a mammal following fibrinolytic therapy or angioplasty, which comprises internally administering an effective amount of a compound of the invention. This invention is also a method for treating stroke, transient ischemia attacks, or myocardial infarction.


DETAILED DESCRIPTION OF THE INVENTION

Although not intending to be bound to any specific mechanism of action, the compounds o

REFERENCES:
patent: 4297346 (1981-10-01), Rips et al.
patent: 4322436 (1982-03-01), Korosi et al.
patent: 4327026 (1982-04-01), Branca et al.
patent: 4361511 (1982-11-01), Branca et al.
patent: 4377522 (1983-03-01), Branca et al.
patent: 4410520 (1983-10-01), Watthey et al.
patent: 4604389 (1986-08-01), Reiffen et al.
patent: 4737495 (1988-04-01), Bomhard et al.
patent: 4808713 (1989-02-01), Attwood et al.
patent: 4820834 (1989-04-01), Evans et al.
patent: 5008263 (1991-04-01), Cooper et al.
patent: 5017571 (1991-05-01), Hansen et al.
patent: 5059688 (1991-10-01), Effland et al.
patent: 5096900 (1992-03-01), George et al.
patent: 5149699 (1992-09-01), Ellingboe et al.
patent: 5241065 (1993-08-01), Berger et al.
patent: 5250679 (1993-10-01), Blackburn et al.
patent: 5403836 (1995-04-01), Blackburn et al.
patent: 5438118 (1995-08-01), Callahan et al.
patent: 5470849 (1995-11-01), Callahan et al.
patent: 5565449 (1996-10-01), Blackburn et al.
patent: 5663166 (1997-09-01), Blackburn et al.
patent: 5674863 (1997-10-01), Blackburn et al.
patent: 5674865 (1997-10-01), Blackburn et al.
patent: 5693636 (1997-12-01), Bondinell et al.
Friedinger, R.M., Cholecystokinin and Gastrin Antagonists, Med. Res. Rev., 9, 271 (1989).
Mori et al., New Synthesis of Diazepinone Skeleton Using Palladium Catalyzed Carbonylation, Heterocycles, 16 (1981).
Muller et al., Synthese von 1, 2-annelierten 1,4-Benzodiazepinen und 4, 1-Benzoxazepinen, Helv. Chim. Acta, 65, 2118 (1982).
Heindel et al., Synthesis, Transformation and General Pharmacologic Activity in 1,4-Benzodiazepine-3,5-Diones, J. Med. Chem., 14, 1233 (1971).
Pauwells et al., Potent and Selective Inhibition of HIV-1 Replication in vitro by a Novel Series of TIBO Derivatives, Nature, 343, 470 (1990).
Nichols et al., J. Pharm. Exp. Ther., 270, 614 (1994).
Coller, Coronary Artery Disease, 3, 1016 (1992).
Topol et al. Thrombosis and Haemostasis, 70, 94 (1993).
Nichols et al., TIPS, 13, 413 (Nov. 1991).
Callahan et al., Peptide Chemistry 1992: Proceedings of the 2nd Japanese Symposium on Peptides Chemistry, p. 495 (1993).
Ku et al., J. Am. Chem. Soc., 115, 8861-8862 (1993).
Sternbach, L.H., J. Med Chem., 22, 2 (1979).
Tighneanu et al., Double Cyclisation of Phenyglycine-o-carboxylic Acids-I, Tetrahedron, 36, 1385 (1980).
Tidwell et al., Thrombosis Research, vol. 19, pp. 339-349 (1980).
Ku et al., J. Med. Chem., 38(1), pp. 9-12 (1995).

LandOfFree

Say what you really think

Search LandOfFree.com for the USA inventors and patents. Rate them and share your experience with other people.

Rating

Bicyclic fibrinogen antagonists does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Bicyclic fibrinogen antagonists, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Bicyclic fibrinogen antagonists will most certainly appreciate the feedback.

Rate now

     

Profile ID: LFUS-PAI-O-96354

  Search
All data on this website is collected from public sources. Our data reflects the most accurate information available at the time of publication.