Dialkyl bicyclic heterocycles with a bridgehead nitrogen as purine analogs possessing significant cardiac inotropic activity

Abstract

A number of 5,7‐dialkyl‐s‐triazolo[1,5‐a]pyrimidines and 5,7‐dialkylpyrazolo[1,5‐a]pyrimidines and related heterocycles containing a bridgehead nitrogen have been prepared and studied as cardiovascular agents in the anesthetized dog. A number of these compounds have exhibited significant inotropic activity with little effect on heart rate. Especially active were 5,7‐dialkyl‐2‐amino or 2‐alkylthio‐s‐triazolo[1,5‐a]pyrimidines. In contrast, highly polar purine analogs in these ring systems compounds such as 5,7‐di‐n‐propyl‐2‐benzylthio‐1,3,4‐thiadiazolo[3,2‐a]pyrimidine bromide 45 containing a charge on the bridgehead nitrogen, were inactive. The detailed structure activity relationship of the dialkyl derivatives of related ring systems are discussed. The presence of certain ring nitrogen atoms are vital to potent in vivo activity, presumably due to specific enzyme binding at these sites. Several of the compounds studied, showed oral activity and are excellent can‐diates for further evaluation in man.

Synthesis and Anti-tumor Activities of Novel [1,2,4]triazolo[1,5-a]pyrimidines

“…Following the procedure reported by Okabe [18], condensation of 1 with ethyl acetoacetate was carried out in acetic acid at reflux to give a mixture of 2 and 2′(the acetylated product of 2), which further treated with methanolic ammonia to give 2 in 88% yield. Subsequent treatment of 2 with phosphorus oxychloride afforded 3 in 94% yield.…”

“…Subsequent aminomethylation of 5a-5c with various secondary amines and formaldehyde, followed by chromatographic purification gave the final products (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) in 45-80% yields.…”

“…All target compounds (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) Table 1 shows that both substituents on the aniline ring and variations on 5"-furylmethyl of the side-chain have substantial influence on the anti-tumor activity. 3-Fluoro-phenylamino substituted series showed comparable or better anti-tumor activities than phenylamino substituted series (comparison of 7 and 11, 8 and 12).…”

“…Therefore, we carried out a series of modifications upon the [1,2,4]triazolo [1,5-a]pyrimidine scaffold by introducing functional groups into C-2 and C-7 positions. Herein, we report the synthesis and in vitro anti-tumor evaluation of a new series of 7-anilino-5-methyl-2-(3-((5-(substituted-aminomethyl)furan-2-yl)methylthio)propyl) [1,2,4]triazol [1,5-a]pyrimidines (6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20).…”

Synthesis and Cytotoxicity Studies of Novel [1,2,4]Triazolo[1,5-a]pyrimidine-7-amines

“…Commercially available g-butyrolactone was treated with aminoguanidine carbonate in pyridine to give the 5-amino-3-(3-hydroxypropyl)-4H-[1,2,4]-triazole 2 in 40% yield exclusively. As described in literature, 11) cyclization of 2 with ethyl acetoacetate was carried out in acetic acid at reflux to afford the 3Ј-hydroxy acetylized intermediate, which was converted to hydroxylate 3 by further reaction with ammonia in methanol in 88% yield. Subsequent treatment of 3 with excess phosphorus oxychloride afforded chloro derivative 4, a key synthon for further elaboration, in 94% yield.…”