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 alkylation followed by detosylation of N6-alkyl-2'-O-tosyl cAMPs (4) which were obtained by the reductive alkylation of 2 with aldehydes in the presence 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.
Kataoka
S
S
Research and Development Division, Kikkoman Corporation, Chiba, Japan.
Yamaji
N
N
Kato
M
M
Kawada
T
T
Imai
S
S
D000478:Alkylation; D000818:Animals; D002316:Cardiotonic Agents / Q000138:chemical synthesis*; D000242:Cyclic AMP / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects*; D066298:In Vitro Techniques; D008297:Male
D002316:Cardiotonic Agents; D000242:Cyclic AMP