Studies on the Syntheses of N-Heterocyclic Compounds. XXVIII. Syntheses of Pyrido [3,4-d] pyridazine Derivatives. (4)

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A variety of 7,8-disubstituted 1,4-dimorpholinopyrido [3,4-d] pyridazine derivatives were synthesized in connection with the structure-activity relationships on diuretic activity. 1,4-Dipolar cycloaddition of 4-alkyl- and 4-benzyl-5-ethoxyoxazoles with dimethyl maleate afforded dimethyl 6-alkyl- and 6-benzyl-5-hydroxy-pyridine-3,4-dicarboxylate (3), which were alkylated to give the corresponding 5-alkoxypyridine derivatives (4). The cycloaddition of 5-alkyl- or 5-benzyl-4-phenyloxazole (9) with N-phenylmaleimide gave an adduct (10), heating of which under acidic condition effected dehydration to give 5-alkyl- or 5-benzyl-N, 6-diphenylpyridine-3,4-dicarboximide (11). Reactions of 4 and 11 with hydrazine gave pyrido [3,4-d] pyridazine-1,4 (2H, 3H)-dione derivatives (5 and 12), chlorination of which followed by substitution with morpholine afforded 7-alkyl- and 7-benzyl-8-alkoxy-pyrido [3,4-d] pyridazine derivatives (7a-k) and 8-alkyl- and 8-benzyl-7-phenyl derivatives (14a, 14b, and 14c). Also prepared were 8-methyl-7-substituted phenyl (14d and 15), 8-chloro- (19 and 21), 8-alkoxy-7-phenyl (26a, 26b, and 26c), and 7-methyl-8-phenyl (43) derivatives. Stereochemistry of the adduct (8) obtained by the 1,4-cyclo-addition reaction of 4-phenyloxazole and N-phenylmaleimide was discussed.
公益社団法人日本薬学会の論文
1976-11-25