Studies on antidiabetic agents. IV. Synthesis and activity of the metabolites of 5-(4-(1-methylcyclohexylmethoxy)benzyl)-2,4-thiazolidinedione (ciglitazone).

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Abstract
Compounds possessing a hydroxy or an oxo moiety on the cyclohexane ring of 5-[4-(1-methylcyclohexylmethoxy)benzyl]-2,4-thiazolidinedione (1, ciglitazone) were synthesized to clarify the structure of the metabolites of 1 and for studies of their pharmacological properties. Of the metabolites identified, 5-[4-(t-3-hydroxy-1-methyl-r-1-cyclohexylmethoxy)benzyl]-2,4-thiazolidinedione (7) exhibited extremely potent antidiabetic activity [in mice] compared to 1. Stereoselective syntheses of 3- or 4-hydroxy-1-methylcyclohexanecarboxylic acids required for the preparation of 3''- or 4''-hydroxylated compounds are described.