Studies on disease-modifying antirheumatic drugs. III. Bone resorption inhibitory effects of ethyl 4-(3,4-dimethoxyphenyl)-6,7-dimethoxy-2-(1,2,4-triazol-1-ylmethyl)quinoline-3-carboxylate (TAK-603) and related compounds

In the course of our studies aimed at obtaining new drugs for treatment of bone and joint diseases, chemical modification of the potent bone resorptio n inhibitors justicidins, was performed and various naphthalene lactones, q uinoline lactones and quinoline derivatives bearing an azole moiety at the side chain were prepared. Their inhibitory effects on bone resorption were evaluated by Raisz's method, and several compounds, including ethyl 4-(3,4- dimethoxyphenyl)-6,7-dimethoxy-2-(1,2,4-triazol-1-ylmethyl)quinoline-3-carb oxylate (6c, TAK-603), were found to have activities comparable with or sup erior to the justicidins. The 4-(3-isopropoxy-4-methoxy)phenyl derivative ( 6d), in particular, displayed a marked increase in potency. TAK-603 and com pound 6d were very effective in preventing osteoclast formation and bone re sorption by mature osteoclasts. Further, TAK-603 was shown to be effective in preventing bone loss in ovariectomized mice.