A series of 5-(naphthalenylsulfonyl)-2,4-thiazolidinediones were synthesized and evaluated for antihyperglycemic activity in an insulin-resistant, genetically diabetic db/db mouse model of non-insulin-dependent diabetes mellitus (NIDDM). The sulfones could be synthesized by a novel, selective C-5 sulfonylation of dilithio-2,4-thiazolidinedione with appropriate sulfonyl chlorides. Within this series, naphthalene was found to be superior to other groups for eliciting antihyperglycemic activity, including the p-alkoxyphenyl group found in ciglitazone, a prototypical agent for this activity. Attachment of the 5-sulfonyl-2,4-thiazolidinedione moiety to the 2-naphthalene position led to optimum activity. Other linkers between the naphthalene and 2,4-thiazolidinedione rings, such as thio, methylene, oxy, and sulfinyl led to decreased antihyperglycemic activity. The best analogue, 5-(2-naphthalenylsulfonyl)-2,4-thiazolidinedione (AY-31,637) was equipotent to ciglitazone in two animal models of NIDDM.

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Synthesis of 3-Mercapto-2(5H)-furanones via Reaction of Dilithio-2,4-thiazolidinedione with α-Halo Ketones.-Dilithio-2,4thiazolidinedione generated by treatment of 2,4-thiazolidinedione (I) with n-butyllithium undergoes reaction with the . alpha.-halo ketones (II) to yield the allylic alcohols (III) and (IV). These products are further transformed into alkylated allylic alcohols such as (IIIf) or 5-hydroxy-2-mercaptofuranones such as (VIII). ( Mechanism). -(ZASK, A.; NOWICKI, J. W.; JIRKOVSKY, I.; VAN ENGEN, D.; Tetrahedron Lett. 34 (1993) 17, 2719-2722; Dep. Med.