Synthesis of new 2,4-diamino-7H-pyrrolo2,3-dpyrimidines via the taylor ring transformation/ring annulation strategy

摘要

Selected examples, 2,4-diamino-7H-pyrrolo2,3-dpyrimidines with a phenyl or benzyl group at the 5-position were synthesized as inhibitors of dihydrofolate reductase (DHFR) from Pneumocystis carinii and Toxoplasma gondii, two potentially life-threatening opportunistic pathogens associated with AIDS and other disorders of the immune systems. Aldol condensation of paraformaldehyde with substituted benzaldehydes or with phenylacetaldehyde affordes #alpha#-hydroxyketones with a phenyl or benzyl group at the 4-position. Further reaction of the hydroxyketones with malononitrile afforded 2-aminofuran-3-carbonitriles, which upon heating with guanidine underwent ring transformation/ring annulation to produce 2,4-diamino-7H-pyrrolo2,3-dpyrimidines rather than 2,4-diaminofuro2,3-dpyrimidines. One of the target compounds obtained in this manner, 2,4-diamino-5-(3,4,5-trimethoxyphenyl)-7H-pyrrolo2,3-dpyrimidine (1d), may be viewed as a conformationally restricted analogues of trimethoprim, an antimicrobial agent widely used in combination with a sulfa drug to treat P.carinii and T.gondii opportunistic infection in patients with AIDS. Compound 1d inhibited P.carinii and T.gondii DHFR with IC_(50) values of 8.3 and 14 #mu#M, respectively. This potency was somewhat greater than that of trimethoprim. However, because this compounds was also more potent than trimethoprim against mammalian (rat liver) DHFR rat liver it lacked species selectivity. The other 2,4-diamino-7H-pyrrolo2,3-dpyrimidines synthesized were neither potent nor selective.