Synthesis of 2,4-diaminopyrido[2,3-d]pyrimidines and 2,4-diamino-quinazolines with bulky dibenz[b,f]azepine and dibenzo[a,d]-cycloheptene substituents at the 6-position as inhibitors of dihydrofolate reductases from Pneumocystis carinii, Toxoplasma gondii, and Mycobacterium avium

Article abstract of DOI:10.1002/jhet.5570370440

The synthesis of four previously undescribed 2,4-diaminopyrido[2,3-d]pyrimidines (3,4) and 2,4-diaminoquinazolines (5,6) with a bulky tricyclic aromatic group at the 6-position is described. Condensation of dibenz[b,f]azepine with 2,4-diamino-6-bromomethylpyrido[2,3-d]pyrimidine (8) and 2,4-diamino-6-bromomethylquinazoline (17) in the presence of sodium hydride afforded N-[(2,4-diaminopyrido[2,3-d]-pyrimidin-6-yl)methyl]dibenz[b,f]azepine (3) and N-[(2,4-diaminoquinazolin-6-yl)methyl]dibenz[b,f]-azepine (4), respectively. Condensation of 5-chlorodibenzo[a,d]cycloheptene (19) and 5-chloro-10,11-dihydrodibenzo[a,d]cycloheptene (20) with 2,4,6-triaminoquinazoline (13) afforded 5-[(2,4-diamino-quinazolin-6-yl)amino]-5H-dibenzo[a,d]cycloheptene (5) and the corresponding 10,11-dihydro derivative (6), respectively. The bromides 8 and 17, as hydrobromic acid salts, were obtained from the corresponding nitriles according to a standard three-step sequence consisting of treatment with Raney nickel in formic acid followed by reduction with sodium borohydride and bromination with dry hydrogen bromide in glacial acetic acid. Compounds 3-6 were evaluated in vitro for the ability to inhibit dihydrofolate reductase from Pneumocystis carinii, Toxoplasma gondii, Mycobacterium avium, and rat liven Compounds 3 and 4 were potent inhibitors of all four enzymes, with IC₅₀ values in the 0.03-0.1 μM range, whereas 5 was less potent. However the selectivity of all four compounds for the parasite enzymes relative to the rat enzyme was <10-fold, whereas the recently reported lead compound in this series, N-[(2,4-diaminopteridin-6-yl)methyl]dibenz[b,f]azepine (1) has >100-fold selectivity for the T. gondii and M. avium enzyme and 21-fold selectivity for the P. carinii enzyme.