Organic compounds -- part of the class 532-570 series – Organic compounds – Unsubstituted hydrocarbyl chain between the ring and the -c-...
Patent
1998-03-09
1999-06-29
Kight, John
Organic compounds -- part of the class 532-570 series
Organic compounds
Unsubstituted hydrocarbyl chain between the ring and the -c-...
540607, 546187, 546189, 546194, 546226, C07D40112, C07D40114, C07D40514, C07D40914
Patent
active
059170344
DESCRIPTION:
BRIEF SUMMARY
This invention relates to a series of N-amidinopiperidine and benzamidine 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 haemostasis 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 alternative structures; for example, WO-A-95/13274 discloses amidinophenylalanine and amidinopyridylalanine derivatives as antithrombotic agents. Further variations on the theme of arginine mimicry amongst thrombin inhibitors are represented by, inter alia, the guanidinyl- and amidinyl-substituted heterocyclic compounds disclosed in EP-A-0623595.
The compounds of the present invention are potent thrombin inhibitors, 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): ##STR1## pharmaceutically acceptable salts thereof, and pharmaceutically acceptable solvates of either entity, optionally substituted with C.sub.1 -C.sub.4 alkyl; alkyl; -C.sub.4 alkylene; optionally methylene-bridged C.sub.5 -C.sub.8 cycloalkyl optionally substituted with one to three C.sub.1 -C.sub.4 alkyl groups or with hydroxy; C.sub.5 -C.sub.8 alkenyl; alkyl; piperidyl N-substituted with C.sub.1 -C.sub.4 alkyl; tetrahydrothiopyranyl or tetrahydropyranyl; C.sub.1 -C.sub.4 alkoxy or with hydroxy; attached, form a piperidine ring which is optionally substituted with C.sub.1 -C.sub.4 alkyl or is optionally benzo-fused.
In the above definition, unless otherwise indicated, alkyl and alkoxy groups having three or more carbon atoms and alkenyl groups having four or more carbon atoms may be straight-chain or branched-chain.
The compounds of formula (i) contain two or more asymmetric centres and th
REFERENCES:
patent: 5346907 (1994-09-01), Kerwin, Jr. et al.
patent: 5561146 (1996-10-01), Kim et al.
Alig et al, Chemical Abstract vol. 118, No. 125071, "N-Acyl-Alpha Amino Acids Method for Their Preparation and Then Use for the Treatment of Diseases" 1992.
Brown Alan Daniel
Danilewicz John Christopher
Fish Paul Vincent
Benson Gregg C.
Covington Raymond
Kight John
Olson A. Dean
Pfizer Inc.
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