(2-Piperidine)- and (2-pyrrolidine)ethanones and -ethanols as inhibitors of blood platelets aggregation

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Abstract
(E)-4-[4-(Methylthio)phenyl]-1-(2-piperidinyl)-3-buten-2-one hydrochloride (44, RMI 14 133A) inhibited ADP-induced aggregation of blood platelets. It was selected from a large series of (2-piperidinyl)- and (2-pyrrolidinyl)ethanones synthesized by a modified Schoepf reaction from enolate magnesium salts of .beta.-keto acids and 2,3,4,5-tetrahydropyridine trimer or 3,4-dihydro-2H-pyrrole trimer, respectively. Evaluation of the compounds was carried out in vitro on human blood platelets. Structure-activity relationships are discussed; 44 inhibited platelet aggregation ex vivo in guinea pigs. Subacute toxicity evaluation in dogs and guinea pigs showed it to have an unfavorable therapeutic ratio. 1-[4''-Chloro(1,1''-biphenyl)-4-yl]-2-(2-piperidinyl)ethanone hydrochloride (18, RMI 12436A) apparently lowered serum cholesterol levels in rats with concurrent accumulation of (3.beta.)-cholesta-5,7-dien-3-ol, suggesting inhibition of 7-dehydrocholesterol .DELTA.7-reductase. [Physiologically platelet aggregation precedes clot formation, inhibition of platelet aggregation may also inhibit arterial thrombosis.].