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Hydrazine derivatives of several pyrazolo[1,5-alpha]pyrimidines (A), pyrazolo[1,5-alpha]-1,3,5-triazines (B), s-triazolo[1,5-alpha]pyrimidines (C), and imidazo[1,2-alpha]pyrimidines (D) were synthesized and condensed with 5-nitrofurfural in order to obtain the corresponding nitrofurfural hydrazones of each heterocycle (1d-14d). Each compound was screened for in vitro activity against Trypanosoma cruzi. The compounds were then tested in vivo against experimental infections of T. cruzi in laboratory (C3H/He strain) mice. An interesting structure-activity relationship was uncovered, revealing that 5-methyl-7-(5-nitrofurfurylidenehydrazino)pyrazolo[1,5-alpha]pyrimidine (2d) greatly increased the mean survival time (IMST) of mice with terminal infections. Subtle alterations in the structure of 2d, such as the substitution of a 5-hydrogen for the 5-methyl group (1d) or the substitution of the 3-hydrogen by the water-soluble 3-sulfonic acid (3d) or 3-sodium sulfonate (4d), resulted in a drastic loss of in vivo and in vitro activity.

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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.

Preparative Buffered Formolysis of 1-ONs.-To 30 ml of 0.103 M potassium formate-formic acid solution, which had been prepared and kept in a nitrogen atmosphere, was added 82 mg (0.247 mmol) of 1-ONs. The solution was placed in a constanttemperature bath at 60.00 ± 0.05°for 20 hr (approximately 10 h/j). It was then cooled and placed in a separatory funnel with 50 ml of ether. The ether solution was washed with four 20-ml portions of water, two 10-ml portions of 7% sodium bicarbonate solution, and 25 ml of water and dried (Na2S04). Removal of solvent gave a residue which was short-path distilled [40-45°( 10-8 mm)] yielding 40.5 mg (97%) of 2-02CH: ir (thin film) 1720 cm-1 (C=Q); nmr (CC14, internal TMS) 1.95 (s, 02CH, 1), 2.65-3.05 (m, aromatic H's, 4), 5.1-5.2 (d, CH02CH, 1), . 4-6.6 (m, ezo-methylene , 1), 6.75 (d, bridgehead H's, 2), and 7.5-7.7 (t, endo-methylene H, 1); the chemical shifts and peak multiplicities agree closely with those of 2-0Ac.6Anal.