One-step synthesis of novel 2,4-diaminopyrimidine antifolates from bridgedalicyclic ketones and cyanoguanidine

A convenient one-step reaction with cyanoguanidine was used to convert alic yclic ketones to previously undescribed 2,4-diamino-5,6,7,8-tetrahydroquina zolines with a one-, two-, or three-carbon bridge in the carbocyclic ring. Although the yields of the desired products were modest, the principal adva ntage of this one-step process was that it provided easy access to a variet y of novel bridged heterocyclic ring systems whose synthesis from stericall y hindered ketones by other methods would have required multiple steps with an even lower overall yield. The products were tested as inhibitors of dih ydrofolate reductases from Pneumocystis carinii, Toxaplasma gondii, and rat liver with a view to examining the effect of a space-filling bridge on bin ding. The most potent and selective compound in the group was 4,6-diamino-3 ,5-diazatricyclo[7.2.1.0(2,7)] dodeca-2,4,6-triene (13), whose potency and selectivity approached those of trimethoprim, a drug commonly used to treat P. carnii and T. gondii infection. 3,5-Diamino-4,6-diazatricyclo[6.2.1.0(2 ,7)]-undeca-2,4,6-triene (14), the analog of 13 with a one-carbon rather th an a two-carbon bridge showed similar potency and selectivity against the T . gondii enzyme, but was a weak and nonselective inhibitor of P. carinii di hydrofolate reductase. The other compounds tested were likewise weak and no nselective.