Phenyl amidines lactones useful as platelet aggregation inhibito

Details Phenyl amidines lactones useful as platelet aggregation inhibito Phenyl amidines lactones useful as platelet aggregation inhibito

1994-05-25

1995-08-15

Ivy, C. Warren

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

514456, 514471, 548204, 549285, 549289, 549290, 549295, 549313, A61K 31425, C07D311012

Patent

active

054419743

DESCRIPTION:

BRIEF SUMMARY
FIELD OF THE INVENTION

This appliation is a 371 of PCT/US92/10526 filed Dec. 11, 1992.
This invention is in the field of mammalian therapeutics and relates to compounds for the treatment of mammalian disorders such as cardiovascular disorders. Of particular interest is a class of phenyl amidines derivatives useful as inhibitors of platelet aggregation.


Background of the Invention

Fibrinogen is a glycoprotein present as a normal component of blood plasma. It participates in platelet aggregation and fibrin formation in the blood clotting mechanism.
Platelets are cellular elements found in whole blood which also participate in blood coagulation. Fibrinogen binding to platelets is important to normal platelet function in the blood coagulation mechanism. When a blood vessel receives an injury, the platelets binding to fibrinogen will initiate aggregation and form a thrombus. Interaction of fibrinogen with platelets occurs through a membrane glycoprotein complex, known as gp IIb/IIIa; this is an important feature of the platelet function. Inhibitors of this interaction are useful in modulating platelet thrombus formation.
It is also known that another large glycoprotein named fibronectin, which is a major extracellular matrix protein, interacts with fibrinogen and fibrin, and with other structural molecules such as actin, collagen and proteoglycans. Various relatively large polypeptide fragments in the cell-binding domain of fibronectin have been found to have cell-attachment activity. See U.S. Pat. Nos. 4,517,686; 4,589,881; and 4,661,111. Certain relatively short peptide fragments from the same molecule were found to promote cell attachment to a substrate when immobilized on the substrate or to inhibit attachment when in a solubilized or suspended form. See U.S. Pat. Nos. 4,578,079 and 4,614,517.
In U.S. Pat. No. 4,683,291, inhibition of platelet function is disclosed with synthetic peptides designed to be high affinity antagonists of fibrinogen binding to platelets. U.S. Pat. No. 4,857,508 discloses tetrapeptides having utility as inhibitors of platelet aggregation.
Other synthetic peptides and their use as inhibitors of fibrinogen binding to platelets are disclosed by Koczewiak et al., Biochem. 23, 1767-1774 (1984); Plow et al., Proc. Natl. Acad. Sci. 82, 8057-8061 (1985); Ruggeri et al., Ibid. 83, 5708-5712 (1986); Ginsberg et al., J. Biol. Chem. 260 (7), 3931-3936 (1985); Hayerstick et al., Blood 66 (4), 946-952 (1985); and Ruoslahti and Pierschbacher, Science 238, 491-497 (1987). Still other such inhibitory peptides are disclosed in EP Patent Applications 275,748 and 298,820.
U.S. Pat. No. 4,879,313 discloses compounds useful as inhibitors of platelet aggregation having the formula: ##STR2## wherein x=6to 10, groups, or an unsubstituted phenyl, biphenyl, naphthyl, pyridyl or thienyl group, and
U.S. Pat. No. 4,977,168 discloses compounds having the following structural formula: ##STR3## wherein R.sub.1 represents hydrogen, a lower alkyl group, a lower hydroxyalkyl group, a benzyl group, a phenyl group or a 4-hydroxyphenyl group; group, or a lower alkoxycarbonylalkyl, lower carboxyalkyl, or lower hydroxyalkyl group; or lower hydroxyalkyl radical, lower alkenyl or lower alkynyl radical or form together with the nitrogen to which they are attached, a saturated heterocycle such as morpholino, thiomorpholino, pyrrolidino not substituted or substituted by an alkoxycarbonyl or carboxy group, piperazino, 4-(lower alkyl)piperazino, 4-(lower hydroxyalkyl)piperazino, or piperidino not substituted or substituted by one of the following groups: lower alkyl, benzyl, hydroxy, lower hydroxyalkyl, amino, lower aminoalkyl, hydroxyamino, alkoxycarbonyl or carboxy. substituted, or a heteroaryl group chosen from the radicals pyridyl, quinolinyl, or isoquinolinyl, possibly substituted, as well as their isomers and their mixtures and their salts with pharmaceutically acceptable mineral or organic acids distinct from the present invention because they lack the lactone moiety of the present invention.
U.S. Pat. No. 4,791,102 d

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E. Plow et al. The Effect of ARG-GLY-ASP-Containing Peptides, etc. Proc. Nat'l Acad. Sci., USA 82, 8057-8061 (Dec. 1985).
M. Ginsberg et al. Inhibition of Fibronectin Binding to Platelets, etc. The Journal of Biological Chemistry, 260(7), 3931-3936 (Apr. 1985).
D. Haverstick et al. Inhibition of Platelet Adhesion to, etc. Blood 66(4) 946-952 (Oct. 1985).
E. Ruoslahti et al. New Perspectives in Cell Adhesion: RGD and, etc. Science, 23 491-497 (Oct. 1987).
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