Synthesis and enzymic activity of 6-carbethoxy- and 6-ethoxy-3,7-disubstituted pyrazolo[1,5-a]pyrimidines and related derivatives as adenosine cyclic 3',5'-phosphate phosphodiesterase inhibitors

Abstract

A number of 3,7-disubstituted 6-carbethoxypyrazolo [1,5-a] pyrimidines and 3,7-disubstituted 6-ethoxypyrazolo-[1,5-a]pyrimidines have been prepared and evaluated as adenosine cyclic 3',5'-phosphate (cAMP) phosphodiesterase (PDE) inhibitors vs. the low Km enzyme isolated from beef heart, rabbit lung, and kidney preparations. The results were found to be between 0.5 to 13 times as potent as theophylline as inhibitors of PDE, depending on the tissue source. A number of these PDE inhibitors exhibited significant physiological effects in different animal systems, suggesting it should be possible to obtain selective PDE inhibition in various tissues. Several of these heterocycles were found superior to adenosine in inhibiting ADP-induced platelet aggregation in vitro.

Improved Synthesis of Substituted 6,7-Dihydroxy-4-quinazolineamines: Tandutinib, Erlotinib and Gefitinib

“…Using formamidine acetate and 2-methoxyethanol as a solvent, we obtained 8 in 85 % yields and >98 % HPLC purity. For the chlorination step we found that the use of thionyl chloride and DMF [6] gave less reliable results than our method using phosphoryl chloride and N,N-diethylaniline [7] where we obtained 70-86 %. The preparation of 9 is not mentioned in the literature.…”

“…Attempts to prepare the desired chloro compound using thionyl chloride and DMF [9] gave only unsatisfactory yields. Similar to the syntheses described above, phosphoryl chloride and N, N-diethylaniline [7] proved to be advantageous. Each of the following steps could be improved substantially and the overall yield from 16 to 3 was 33 % as compared to 20 % previously [9].…”

“…Nitration of 11 gave the desired regioisomer on 92% yield and was followed by catalytic hydrogenation and cyclization with formamide performed according to the patent literature [8]. Again, our preferred reagent for the chlorination was phosphoryl chloride and N,N-diethylaniline [7], giving 15 in 89 % yield and 96 % HPLC purity. The final product was obtained as the hydrochloride salt 2·HCl and converted to 2.…”

EMCA and DEEM as Michael Reagents Used in Organic Synthesis

“…Unsubstituted or 4-alkylsubstituted 3-aminopyrazoles reacted with DEEM in acetic acid [142][143][144] giving 7-oxopyrazolo[1,5-a]pyrimidine-6-carboxylates (28) (Fig. 27), the adenosine cyclic 3',5'-phosphate phosphodiesterase inhibitors [142]. 3-aminopyrazole-4-ones under same conditions gave 4,7-dioxopyrazolo[1,5-a]pyrimidine-6-carboxylates (29) (Fig.…”

The Chemistry of Alkenyl Nitriles and its Utility in Heterocyclic Synthesis

“…Pyrans were readily obtained in good yields on treatment of ylidene derivatives of α-cyanochalcones with active methylene nitriles and active methylene ketones. Thus, benzylidene derivatives, aminomethylene and mercaptomethylene derivatives has been reported [170,235,236] to react with active methylene reagents to yield pyran derivatives [266][267][268][269][270][271][272].…”