Studies on the Synthesis of Compounds Related to Adenosine 3', 5'-Cyclic Phosphate. VII. : Synthesis and Cardiac Effects of N6, N6-Dialkyl Adenosine 3', 5'-Cyclic Phosphates

A series of novel N6, N6-dialkyl adenosine 3', 5'-cyclic phosphates (N6, N6-dialkyl cAMPs) was synthesized from 2'-O-p-toluenesulfonyl cAMP (2'-O-tosyl cAMP, 2) and tested for inotropic and chronotropic activities in vitro.Treatment of 2 with excess alkyl halides and sodium hydride followed by detosylation with aqueous NaOH readily gave N6, N6-dialkyl cAMPs (3) in good yields. Various N6, N6-dialkyl cAMPs having different alkyl groups at the N6-position (9-12) were prepared by alkylatin followed by detosylation of N6-alkyl-2'-O-tosyl cAMPs (4) which were obtained by the reductive alkylation of 2 with aldehydes in the presenve of sodium cyanoborohydride in acetic acid or tosylation of N6-methyl cAMP. The mechanism of the detosylation is briefly discussed. Among the N6, N6-dialkylated derivatives, N6, N6-dipentyl (3f) and N6-ethyl-N6-heptyl (10e) derivatives were found to exhibit a potent positive inotropic effect and a weak positive chronotropic effect. The structure-activity relationships for the position and the length of alkyl residue are discussed.