University of California

Rhone-Poulenc Rorer Pharmaceuticals Inc.

Jeffrey M Dener

Henry Rapoport

Bruce F Molino

Scott I Klein

Mark Czekaj

Michael R Becker

Jeffrey C Pelletier

Lin-hau Zhang

This invention relates to novel peptide and pseudopeptide derivatives and analogs of aspartic acid which are useful as inhibitors of platelet aggregation and thrombus formation in mammalian blood, to pharmaceutical compositions including such compounds, and to their use in inhibiting thrombus formation and platelet aggregation in mammals.

Antithrombotic peptides and pseudopeptides

Optically active lactones are described, such as an intermediate lactone having the formula ##STR1## where R and R.sup.2 are each independently alkyl with 1 to 6 carbon atoms, cycloalkyl with 6 to 10 carbon atoms, aryl with 6 to 10 carbon atoms, or arylalkyl with 7 to 19 carbon atoms, R.sup.4 is H or C.sub.1-6 alkyl, and Ar is a homo- or heteroaromatic ring with 5 or 6 ring atoms being optionally substituted by C.sub.1-6 alkyl or alkoxy groups, halogen atoms, cyano or nitro groups. Such optically active, intermediate lactones are prepared from L-aspartic acid, and can be readily converted to (+)-pilocarpine and its analogues by hydrolysis, reduction, and hydrogenation, such as to an optically active lactone having the formula ##STR2## which is (+)-pilocarpine when R is ethyl, R.sup.4 is H, and Ar is 1-methylimidazol-5-yl.

Synthesis of optically active lactones from L-aspartic acid and

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King of Prussia, PA, United States of America

Jeffrey M Dener