1-AZAFAGOMINE - A HYDROXYHEXAHYDROPYRIDAZINE THAT POTENTLY INHIBITS ENZYMATIC GLYCOSIDE CLEAVAGE

ans)-4,5-dihydroxy-3-hydroxymethylhexahydropyrida- zine (16) was synth esized in four steps from 2,4-pentadienol (22) and 4-phenyltriazolin-3 ,5-dione (18) in an overall yield of 32%. In the first step a Diels-Al der reaction between 18 and 22 gave (+/-)-2-hydroxymethyl-8-phenyl- 1, 6,8-triazabicyclo[4.3.0]non-3-ene-7,9-dione (23c) in 88% yield. Epoxid ation of 23c with trifluoromethyl(methyl)dioxirane, generated in situ, gave the trans epoxide 24c in 62 % yield. Hydrolysis of the epoxide w ith perchloric acid gave stereoselectively (2,3-trans-3 ,4-trans)-3,3- dihydroxy-3-hydroxymethyl-8-phenyl-1 ,6,8-triazabicyclo[4.3.0]nonane-7 ,9-dione (26) in 73% yield. In the fourth and final step, hydrazinolys is of 26 Save 16 in 84% yield. Pyridazine 16 was found to be a potent inhibitor of rand beta-glucosidase, isomaltase and glycogen phosphoryl ase, while galactosidases and alpha-mannosidase were not inhibited. Th e inhibition of beta-glucosidase is independent of pH, and was found t o be due to unprotonated 16.