Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1996-04-19
1998-05-12
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514307, 540597, 546145, C07D40112, C07D21700, C07D21716, A61K 3155
Patent
active
057505209
DESCRIPTION:
BRIEF SUMMARY
CROSS-REFERENCE TO RELATED APPLICATIONS
This is the national stage under 35 U.S.C. .sctn.371 of International Patent Application No. PCT/EP94/03509, filed Oct. 24, 1994, claiming priority to Great Britain patent application No. 9322976.3, filed Nov. 8, 1993.
This invention relates to a series of amidinophenylalanine and amidinopyridylalanine derivatives, which are antithrombotic agents, having utility in a variety of therapeutic areas including the prevention and/or treatment of deep vein thrombosis (DVT) after surgery, major medical illness, paralysis, malignancy, prolonged immobilisation trauma, application of lower limb plaster casts, or fractures of the lower limbs or pelvis; recurrent DVT; DVT during pregnancy when there is a previous history thereof; reocclusion following thrombolytic therapy; chronic arterial obstruction; peripheral vascular disease; acute myocardial infarction; unstable angina; atrial fibrillation; thrombotic stroke; transient ischaemic attacks; disseminated intravascular coagulation; coagulation in extra-corporeal circuits; occlusion of arterio-venous shunts and blood vessel grafts (including coronary artery by-pass-grafts); and restenosis and occlusion following angioplasty. They also have utility as an adjunct to thrombolytic therapy.
The compounds of the invention are potent and selective inhibitors of thrombin, which is the final serine protease enzyme in the coagulation cascade. The prime function of thrombin is the cleavage of fibrinogen to produce fibrin which forms linear insoluble polymers which, in turn, are cross-linked by factor XIIIa, itself activated by thrombin. In addition, thrombin regulates its own production by activation of factors V and VIII earlier in the cascade. It also has important actions at the cellular level, where it acts on specific receptors to cause platelet aggregation, endothelial cell activation and fibroblast proliferation. Thus thrombin has a central regulatory role in homeostasis and thrombus formation.
Clearly then, potent, selective and orally bioavailable thrombin inhibitors represent an attractive target for the convenient therapeutic control of thrombosis. In addition, thrombin potently causes neurite retraction and therefore a thrombin inhibitor is of potential therapeutic utility in the treatment of acute and chronic neurodegenerative disorders. Furthermore, the compounds disclosed herein are of potential value in the treatment of inflammatory disorders and scarring, and in wound healing.
Because of their potential as substrate mimics, arginine derivatives have been explored as thrombin inhibitors and this work led to the discovery of argatroban (see Cardiovascular Drug Rev., 1991, 9, 247). In turn, other research groups have sought to express the basic arginine function in a variety of alternative structures; for example, WO-A-92/08709 discloses amidino, guanidino, amidoximino, aminomethyl and amino phenylalanine derivatives as antithrombotic agents.
The compounds of the present invention are significantly more potent thrombin inhibitors than those mentioned above, selective (in comparison with their inhibition of, for example, trypsin, plasmin, butyrylcholinesterase and elastase), well tolerated and orally bioavailable.
Accordingly, the present invention provides a compound of formula (I): ##STR2## pharmaceutically acceptable salts thereof, and pharmaceutically acceptable solvates of either entity, wherein
X is CH or N;
Y is optionally monounsaturated C.sub.3 -C.sub.5 alkylene optionally substituted with C.sub.1 -C.sub.4 alkyl or methylene;
R.sup.1 is H; C.sub.1 -C.sub.4 alkyl optionally substituted with C.sub.1 -C.sub.4 alkoxy, OH, NR.sup.5 R.sup.6, CONR.sup.5 R.sup.6, C.sub.3 -C.sub.6 cycloalkyl or aryl; or C.sub.3 -C.sub.6 alkenyl;
R.sup.2 is H; C.sub.1 -C.sub.4 alkyl optionally substituted with C.sub.1 -C.sub.4 alkoxy, OH, NR.sup.5 R.sup.6, CONR.sup.5 R.sup.6, C.sub.3 -C.sub.6 cycloalkyl or aryl; or CONR.sup.5 R.sup.6 ;
R.sup.3 and R.sup.4 are each independently selected from H; C.sub.1 -C.sub.4 alkyl optionally substituted with
REFERENCES:
patent: 5518735 (1996-05-01), Sturzebecher
Wagner, G. et al., Pharmazie, 36, 9, pp. 597-603 (1981).
Wagner, G. et al., Pharmazie, 39, 4, pp. 226-230 (1984).
Danilewicz John Christopher
Ellis David
Kobylecki Ryszard Jurek
Benson Gregg C.
Pfizer Inc.
Rao Deepak R.
Richardson Peter C.
Ronau Robert T.
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