Isoxazolo-[3,4-d]-pyridazin-7-(6H)-one as a Potential Substrate for New Aldose Reductase Inhibitors

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• 作者：Luca Costantino ; Giulio Rastelli ; M. Cristina Gamberini ; M. Paola Giovannoni ; Vittorio Dal Piaz ; Paola Vianello ; and Daniela Barlocco
• 刊名：Journal of Medicinal Chemistry
• 出版年：1999
• 出版时间：June 3, 1999
• 年：1999
• 卷：42
• 期：11
• 页码：1894 - 1900
• 全文大小：104K
• 年卷期：v.42,no.11(June 3, 1999)
• ISSN：1520-4804

文摘

The isoxazolo-[3,4-d]-pyridazin-7-(6H)-one (2) and its corresponding open derivatives 5-acetyl-4-amino-(4-nitro)-6-substituted-3(2H)pyridazinones (3, 4) were used as simplified substratesfor the synthesis of new aldose reductase inhibitors with respect to the previously reported5,6-dihydrobenzo[h]cinnolin-3(2H)one-2 acetic acids (1). Moreover, a few derivatives lackingthe 5-acetyl group were prepared. Several compounds derived from 2 displayed inhibitoryproperties comparable to those of Sorbinil. In this class the presence at position 6 of a phenylcarrying an electron-withdrawing substituent proved to be beneficial, independently from itsposition on the ring (5g,j-l). Acetic acid derivatives were more effective than propionic andbutyric analogues. On the contrary, all the monocyclic compounds (6-8) were either inactiveor only weakly active. The 3-methyl-4-(p-chlorophenyl)isoxazolo-[3,4-d]-pyridazin-7-(6H)-oneacetic acid (5g), which proved to be the most potent derivative, was also investigated inmolecular modeling studies, to assess possible similarities in its interaction with the enzyme,with respect to the model 1.