Abstract:
:A number of 3-bromo-, 3-nitro-, and 3-ethoxycarbonyl-5,7-dialkylpyrazolo[1,5-a]pyrimidines were synthesized and screened as in vitro cAMP phosphodiesterase inhibitors. The condensation of 3-aminopyrazole with symmetrical beta-diketones (acetylacetone, heptane-3,5-dione, etc.) afforded symmetrical dialkylpyrazolo[1,5-a]pyrimidines (5). The reaction of 3-aminopyrazole with unsymmetrical beta-diketones (hexane-2,4-dione, heptane-3,5-dione, etc.) gave a mixture of 5-methyl-7-alkylpyrazolo[1,5-a]pyrimidine (3) and 5-alkyl-7-methylpyrazolo[1,5-a]pyrimidines (4). The technique for the separation of 3 from 4 is described. The inhibition constants, alpha (the ratio of the molar I50 of theophylline to the molar I50 of the test compounds), were subjected to a Hansch correlation analysis. The results indicated that PDE isolated from beef heart tissue was most sensitive to changes in the length of the alkyl group in the 5 position of the pyrazolo[1,5-a]pyrimidine ring, whereas the PDE isolated from rabbit lung tissue was more sensitive to changes in the length of the 7-alkyl group. Experimentally and theoretically, the n-propyl group was found to approximate the ideal size for the alkyl group in both the 5 and 7 positions;5,7-di-n-propyl-3-ethoxycarbonylpyrazolo[1,5-a]pyrimidine (5e) was the most potent inhibitor of both lung and heart PDE.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Novinson T,Miller JP,Scholten M,Robins RK,Simon LN,O'Brien DE,Meyer RB Jrdoi
10.1021/jm00239a004subject
Has Abstractpub_date
1975-05-01 00:00:00pages
460-4issue
5eissn
0022-2623issn
1520-4804journal_volume
18pub_type
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