4-BENZYLAMINO-1-CHLORO-6-SUBSTITUTED PHTHALAZINES - SYNTHESIS AND INHIBITORY ACTIVITY TOWARD PHOSPHODIESTERASE-5

We synthesized various 4-benzylamino-1-chloro-6-substituted phthalazin es (15) and 4-benzylamino-1-chloro-7-substituted phthalazines (16) and evaluated their inhibitory activity toward phosphodiesterase 5 (PDE5) purified from porcine platelets. The PDE5-inhibitory activities of 15 were greater than those of the isomers (16). The preferred substituen t at the 4-position of phthalazine was a (3-chloro-4-methoxybenzyl)ami no group, and those at the B-position were cyano, nitro, and trifluoro methyl groups. Compounds 15a (IC50 = 4.8 nM), 15f (3.5 nM), and 15i (5 .3 nM) were more potent inhibitors than E4021 (8.6 nM). Compounds 15a and 15f also showed vasorelaxant activity in isolated porcine coronary arteries precontracted with prostaglandin F-2 alpha (10(-5) M). The E C50 values for vasorelaxant action of 15a, 15f, and E4021 were 150, 16 0, and 980 nM, respectively. These results show that novel PDE5 inhibi tors possessing a potent vasorelaxant effect may exist among phthalazi ne derivatives.